AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

Conditions
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Community-acquired Pneumonia

Intervention / Treatment
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* Drug: Heparin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥18 years of age Admitted to hospital for a suspected or confirmed diagnosis of CAP defined by: Radiographic evidence of new or worsening infiltrate One or more of the following signs and/or symptoms of lower respiratory tract infection i. New or increased cough or sputum production ii. Fever of > 37.8C or temperature < 36C iii. WBC > 11 x 109/L or < 4 x 109/L c. The primary diagnosis is believed to be CAP as per the attending physician Requires supplemental oxygen to treat hypoxemia (or requires an increased level of supplemental oxygen if on chronic oxygen therapy) Hospital admission anticipated to last ≥72 hours from randomization Exclusion Criteria: Suspected or confirmed active COVID-19 infection Hospital admission for >72 hours prior to randomization Patients receiving non-invasive or invasive ventilation, vasopressors, or extracorporeal life support (ECLS) within an ICU at the time of enrollment Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization Patients for whom the intent is to not use pharmacologic thromboprophylaxis Patients with an independent indication for therapeutic-dose anticoagulation Patients with a contraindication to therapeutic-dose anticoagulation, including: Non-traumatic bleeding that requires medical evaluation or hospitalization within 30 days prior to CAP hospital admission History of an inherited or acquired bleeding disorder Cerebral aneurysm or mass lesions of the central nervous system Ischemic stroke within 3 months of hospital admission Gastrointestinal bleeding within 3 months of hospital admission Platelet count <50 x109/L OR INR >2.0 OR hemoglobin <80 g/L at the time of screening Other physician-perceived contraindications to therapeutic anticoagulation History of heparin induced thrombocytopenia (HIT) or other heparin allergy Current or recent (within 7 days of screening) use of dual anti-platelet inhibitors (For example; Aspirin + one of the following; clopidogrel, ticagrelor, prasugrel) Patients in whom imminent death is anticipated Anticipated transfer to another hospital that is not a study site within 72 hours of randomization Enrollment in other interventional trials related to anticoagulation or antiplatelet therapy during current hospitalization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Adaptive stratified randomized clinical trial with Bayesian stopping rules
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic-Dose Heparin<br>Participants randomized to the investigational arm will receive a pragmatic strategy of therapeutic-dose low molecular-weight heparin (LMWH) or unfractionated heparin (UFH) administered daily for up to 14 days or until hospital discharge, whichever occurs first. Participants should start receiving study drug as soon as possible following randomization. | Drug: Heparin<br>* 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.<br>|
| No Intervention: Usual Care<br>Participants randomized to the control arm will receive usual care thromboprophylactic dose anticoagulation according to local practice. To ensure adequate separation between the study groups, the dose of heparin/LMWH used in the usual care arm should not equal more than half of the approved therapeutic dose for that agent according to local VTE treatment protocols. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding events | Number of participants with major bleeds as defined by the ISTH definition. | 14 days | 
| HIT events | Number of participants with laboratory confirmed heparin induced thrombocytopenia (HIT) | 14 days | 
| Thrombotic events | Number of participants with deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke | 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 | 30 days | 
| All cause mortality |  | 30 days, 90 days, and 180 days | 
| Hospital-free days | Days alive outside hospital | 30 days, 90 days, and 180 days | 
| Health related quality of life | Using the EQ-5D-5L instrument | 30 days, 90 days, and 180 days | 
| Health related quality of life | Using the Clinical Frailty Scale instrument | 30 days, 90 days, and 180 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumonia, Heparin, Anticoagulation, Community acquired pneumonia, Unfractionated Heparin, Low Molecular Weight Heparin, Dalteparin, Enoxaparin, Tinzaparin