Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19

Gregg W Stone; Michael E Farkouh; Anuradha Lala; Elizabeth Tinuoye; Ovidiu Dressler; Pedro R Moreno; Igor F Palacios; Shaun G Goodman; Rodrigo B Esper; Alexandre Abizaid; Deepak Varade; Juan F Betancur; Alejandro Ricalde; Gerardo Payro; José María Castellano; Ivan F N Hung; Girish N Nadkarni; Gennaro Giustino; Lucas C Godoy; Jason Feinman; Anton Camaj; Solomon W Bienstock; Remo H M Furtado; Carlos Granada; Jessica Bustamante; Carlos Peyra; Johanna Contreras; Ruth Owen; Deepak L Bhatt; Stuart J Pocock; Valentin Fuster; FREEDOM COVID Anticoagulation Strategy Randomized Trial Investigators

doi:10.1016/j.jacc.2023.02.041

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19

J Am Coll Cardiol. 2023 May 9;81(18):1747-1762. doi: 10.1016/j.jacc.2023.02.041. Epub 2023 Mar 6.

Authors

Gregg W Stone¹, Michael E Farkouh², Anuradha Lala¹, Elizabeth Tinuoye¹, Ovidiu Dressler³, Pedro R Moreno¹, Igor F Palacios⁴, Shaun G Goodman⁵, Rodrigo B Esper⁶, Alexandre Abizaid⁷, Deepak Varade⁸, Juan F Betancur⁹, Alejandro Ricalde¹⁰, Gerardo Payro¹¹, José María Castellano¹², Ivan F N Hung¹³, Girish N Nadkarni¹⁴, Gennaro Giustino¹, Lucas C Godoy², Jason Feinman¹, Anton Camaj¹, Solomon W Bienstock¹, Remo H M Furtado¹⁵, Carlos Granada¹⁶, Jessica Bustamante¹, Carlos Peyra¹, Johanna Contreras¹, Ruth Owen¹⁷, Deepak L Bhatt¹, Stuart J Pocock¹⁷, Valentin Fuster¹⁸; FREEDOM COVID Anticoagulation Strategy Randomized Trial Investigators

Affiliations

¹ The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
² Peter Munk Cardiac Centre, University of Toronto, Toronto, Ontario, Canada.
³ Cardiovascular Research Foundation, New York, New York, USA.
⁴ Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ St Michael's Hospital, Unity Heath, University of Toronto, Toronto, Ontario, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada.
⁶ Prevent Senior Institute, São Paulo, São Paulo, Brazil.
⁷ Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
⁸ BAJ RR Hospital, Mumbai, India.
⁹ Clínica Medellín QuirónSalud, Medellín, Colombia.
¹⁰ CITIC, Mexico City, Mexico.
¹¹ Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubiran, Mexico City, Mexico.
¹² Centro Integral de Enfermedades Cardiovasculares (CIEC), Hospital Universitario Monterpincipe, Grupo HM Hospitales, Madrid, Spain.
¹³ The University of Hong Kong, Hong Kong.
¹⁴ The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Data Driven and Digital Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁵ Brazilian Clinical Research Institute, São Paulo, Brazil.
¹⁶ CogenTech Medical and Digital Innovation, Mahwah, New Jersey, USA.
¹⁷ London School of Hygiene and Tropical Medicine, London, United Kingdom.
¹⁸ The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address: [email protected].

Abstract

Background: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results.

Objectives: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19.

Methods: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group.

Results: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent.

Conclusions: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

Keywords: apixaban; coronavirus disease 2019; enoxaparin; prognosis; severe acute respiratory syndrome coronavirus 2.

Publication types

Randomized Controlled Trial

MeSH terms

Anticoagulants / adverse effects
Blood Coagulation
COVID-19*
Enoxaparin / therapeutic use
Humans
Thromboembolism* / chemically induced
Thromboembolism* / prevention & control

Substances

Enoxaparin
Anticoagulants

Associated data

ClinicalTrials.gov/NCT04512079