Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.
This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial
to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for
patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants
will be randomized either to the investigational arm (therapeutic anticoagulation with
heparin for 14 days or until "recovery" [defined as hospital discharge or liberation from
supplemental oxygen if initially required], whichever comes first), or to the control arm
(usual care, including thromboprophylactic dose anticoagulation according to local practice).
Drug: Heparin
Low molecular weight heparin (LMWH) Preferred therapeutic anticoagulant is enoxaparin. Generally regimens: 1.5 mg/kg subcutaneous once daily or 1 mg/kg subcutaneous twice daily. Alternatively, other subcutaneous LMWH used, including tinzaparin (175 anti-Xa IU/kg subcutaneous once daily) or dalteparin (200 IU/kg subcutaneous once daily or 100 IU/kg subcutaneous twice a day).
Unfractionated heparin (UFH) Commenced, administered, and monitored according to local hospital policy, and guidelines that are used for the treatment of venous thromboembolism (i.e. not for acute coronary syndrome). Intravenous infusion of UFH is according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x the reference value. If UFH is used, the availability of a local hospital policy that has specifies an aPTT target in this range or an anti-Xa value is a requirement.
Inclusion Criteria:
1. Patients ≥18 years of age providing (possibly through a substitute decision maker)
informed consent who require hospitalization anticipated to last ≥72 hours, for
microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of
COVID-19 confirmation
• If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak
or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome
attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening
oxygen requirements or acute kidney injury) which is further anticipated to extend the
hospital admission by an additional 72 hours from randomization.
Exclusion Criteria:
1. Patients admitted to an ICU AND receiving organ support (i.e. high flow nasal oxygen,
receiving non-invasive or invasive mechanical ventilation, or are requiring
vasopressor/inotrope)
2. Patients for whom the intent is to not use pharmacologic thromboprophylaxis
3. Active bleeding
4. Risk factors for bleeding, including:
1. intracranial surgery or stroke within 3 months;
2. history of intracerebral arteriovenous malformation;
3. cerebral aneurysm or mass lesions of the central nervous system;
4. intracranial malignancy
5. history of intracranial bleeding
6. history of bleeding diatheses (e.g., hemophilia)
7. history of gastrointestinal bleeding within previous 3 months
8. thrombolysis within the previous 7 days
9. presence of an epidural or spinal catheter
10. recent major surgery <14 days
11. uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)
12. other physician-perceived contraindications to anticoagulation
5. Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50 (if available per SOC
testing)
6. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion
if potential bleeding were to occur)
7. Acute or subacute bacterial endocarditis
8. History of heparin induced thrombocytopenia (HIT) or other heparin allergy including
hypersensitivity
9. Current use of dual antiplatelet therapy
10. Patients with an independent indication for therapeutic anticoagulation
11. Patients in whom imminent demise is anticipated and there is no commitment to active
ongoing intervention
12. Anticipated transfer to another hospital that is not a study site within 72 hours
13. Enrollment in other trials related to anticoagulation or antiplatelet therapy
Emory University Hospital Midtown
Atlanta, Georgia, United States
University of Chicago
Chicago, Illinois, United States
Ochsner Clinic
Jefferson, Louisiana, United States
Maine Medical Center
Portland, Maine, United States
Henry Ford University
Dearborn, Michigan, United States
Beaumont Hospital
Royal Oak, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center
Saint Louis, Missouri, United States
Cooper University Health Care
Camden, New Jersey, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
Saint Barnabas Medical Center
Livingston, New Jersey, United States
Montefiore-Einstein Center for Heart and Vascular Care
New York, New York, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Santa Casa de Misericordia de Itabuna
Itabuna, BA, Brazil
Hospital Unimed do Cariri
Juazeiro do Norte, CE, Brazil
Instituto Goiano de Oncologia e Hematologia - INGOH
Goiania, Goias, Brazil
Centro de Pesquisas Clínicas Humap - UFMS
Campo Grande, Mato Grosso Do Sul, Brazil
Hospital Felício Rocho
Belo Horizonte, MG, Brazil
Clinica de Campo Grande S/A
Campo Grande, MS, Brazil
Unimed Campo Grande
Campo Grande, MS, Brazil
Hospital Agamenon Magalhaes
Recife, Pernanbuco, Brazil
Hospital das Clinicas da UFPR
Curitiba, PR, Brazil
Pontifícia Universidade Católica do Paraná
Curitiba, PR, Brazil
Parana Medical Research Center
Maringa, PR, Brazil
Hospital Sao Vicente de Paulo
Passo Fundo, Rio Grande Do Sul, Brazil
Hospital Universitario Pedro Ernesto
Rio de Janeiro, RJ, Brazil
Hospital de Clinicas de Porto Alegre
Porto Alegre, RS, Brazil
Instituto de Cardiologia do Rio Grande do Sul
Porto Alegre, RS, Brazil
Instituto de Medicina Vascular
Porto Alegre, RS, Brazil
AngioCor Blumenau
Blumenau, Santa Catarina, Brazil
Instituto de Cardiologia de Santa Catarina
Sao Jose, Santa Catarina, Brazil
Instituto de Pesquisa Clínica de Campinas
Campinas, Sao Paulo, Brazil
Praxis Pesquisa Medica
Santo Andre, Sao Paulo, Brazil
Santa Casa de Votuporanga
Votuporanga, Sao Paulo, Brazil
Casa de Saúde Santa Marcelina
Sao Paulo, SP, Brazil
Instituto de Molestias Cardio Vasculares de Tatui
Tatui, SP, Brazil
Hospital 9 de Julho
São Paulo, Brazil
Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo
São Paulo, Brazil
Instituto de Infectologia Emilio Ribas
São Paulo, Brazil
Instituto do Coração do Estado de São Paulo
São Paulo, Brazil
Sociedade Beneficente Israelita Hospital Albert Einstein
São Paulo, Brazil
Victoria General Hospital
Victoria, British Columbia, Canada
Health Sciences Center Winnipeg
Winnipeg, Manitoba, Canada
Grace General Hospital
Winnipeg, Manitoba, Canada
St. Boniface General Hospital
Winnipeg, Manitoba, Canada
Hamilton Health Sciences
Hamilton, Ontario, Canada
St. Joseph's Healthcare Hamilton
Hamilton, Ontario, Canada
Hôpital Montfort
Ottawa, Ontario, Canada
The Ottawa Hospital
Ottawa, Ontario, Canada
University Health Network
Toronto, Ontario, Canada
McGill University Health Centre
Montréal, Quebec, Canada
Centre Hospitalier de l'université de Montréal (CHUM)
Montréal, Quebec, Canada
Jewish General Hospital
Montréal, Quebec, Canada
CHU de Quebec-University Laval
Québec, Quebec, Canada
Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ)
Québec, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada
Regina General Hospital
Regina, Saskatchewan, Canada
Hospital de Infectolog´ñia Centro Médico Nacional La Raza
Azcapotzalco, Mexico City, Mexico
Hospital General Regional 1 Carlos MacGregor Sánchez Navarro
Benito Juárez, Mexico City, Mexico
Hospital General regional 2 El Marqués
Querétaro, Mexico