This is an international, open-label, stratified randomized controlled trial with Bayesian adaptive stopping rules to compare the effects of therapeutic-dose heparin vs. usual care pharmacological thromboprophylaxis on outcomes in patients admitted to hospital with community acquired pneumonia (CAP).
The global incidence of hospitalization due to CAP is high and associated with substantive morbidity and mortality. Thrombotic complications - including venous, arterial, and possibly microvascular - occur commonly in hospitalized patients across many etiologies of CAP. Poor outcomes may be mediated by both inflammatory and thrombotic processes leading to respiratory, cardiac, and other end organ dysfunction. There are currently no established therapies that modify the potentially maladaptive immunothrombosis pathway in CAP. Therapeutic-dose anticoagulation with heparin reduces disease progression and mortality in non-critically ill patients hospitalized with COVID-19 with an acceptable safety profile. COVID-19 shares pathogenic features, including activation of the inflammatory and coagulation cascades, with other pneumonias. Whether therapeutic-dose heparin confers similar clinical benefits in non-COVID-19 CAP is unknown.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
4,000
Preference is for LMWH given ease of administration and possibility of a more favorable safety profile, if no contraindication is present. Enoxaparin, dalteparin, or tinzaparin are acceptable LMWHs to be used for patients in the investigational arm and dose should be based on measured or estimated weight of the patient. Alternatively, intravenous UFH may be used and may be preferred in the presence of significant renal compromise. Intravenous UFH is typically dosed 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, or a corresponding UFH anti-Xa level. If UFH is used, the availability of a local site policy that specifies an aPTT target in this range or a corresponding anti-Xa value is a requirement.
Ordinal endpoint reflecting survival
Survival to hospital discharge without ICU-level organ support. Organ support is defined as receipt of high flow nasal oxygen, invasive or non-invasive mechanical ventilation, vasopressor/inotropic therapy, or extracorporeal life support (ECLS) within an ICU. This outcome reflects disease progression to ICU-level organ failure or the worst possible outcome (death). It was chosen because of its importance to patients, clinicians, and other stakeholders. Given the limited number of ICU beds, reducing the burden of critical illness has important health system capacity implications.
Time frame: 30 days
Bleeding events
Number of participants with major bleeds as defined by the ISTH definition.
Time frame: 14 days
HIT events
Number of participants with laboratory confirmed heparin induced thrombocytopenia (HIT)
Time frame: 14 days
Thrombotic events
Number of participants with deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke
Time frame: 30 days and 90 days
Invasive mechanical ventilation
Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization
Time frame: 30 days
All cause mortality
Time frame: 30 days, 90 days, and 180 days
Hospital-free days
Days alive outside hospital
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University of Chicago
Chicago, Illinois, United States
NOT_YET_RECRUITINGOchsner Clinic
Jefferson, Louisiana, United States
RECRUITINGMaine Medical Centre
Portland, Maine, United States
RECRUITINGHenry Ford Health System
Dearborn, Michigan, United States
COMPLETEDCooper University Health Care
Camden, New Jersey, United States
RECRUITINGMedical College of Wisconsin
Milwaukee, Wisconsin, United States
RECRUITINGHospital Estadual Dr. Jayme Santos Neves
Serra, Espírito Santo, Brazil
RECRUITINGHospital Evangelico de Vila Velha
Vila Velha, Espírito Santo, Brazil
RECRUITINGHospital Universitário Cassiano Antonio Moraes
Vitória, Espírito Santo, Brazil
NOT_YET_RECRUITINGSanta Casa de Misericordia de Itabuna
Itabuna, Estado de Bahia, Brazil
COMPLETED...and 54 more locations
Time frame: 30 days, 90 days, and 180 days
Health related quality of life
Using the EQ-5D-5L instrument
Time frame: 30 days, 90 days, and 180 days
Health related quality of life
Using the Clinical Frailty Scale instrument
Time frame: 30 days, 90 days, and 180 days