AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

Overview

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

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.

Interventions

• Drug Heparin
  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 weigh

Primary outcome measures

• Ordinal endpoint reflecting survival [Time frame: 30 days]

Secondary outcome measures (8)

• Bleeding events [Time frame: 14 days]
• HIT events [Time frame: 14 days]
• Thrombotic events [Time frame: 30 days and 90 days]
• Invasive mechanical ventilation [Time frame: 30 days]
• All cause mortality [Time frame: 30 days, 90 days, and 180 days]
• Hospital-free days [Time frame: 30 days, 90 days, and 180 days]
• Health related quality of life [Time frame: 30 days, 90 days, and 180 days]
• Health related quality of life [Time frame: 30 days, 90 days, and 180 days]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Brazil · 33 centers

• Hospital Estadual Dr. Jayme Santos Neves — Serra
• Hospital Evangelico de Vila Velha — Vila Velha
• Hospital Universitário Cassiano Antonio Moraes — Vitória
• Santa Casa de Misericordia de Itabuna — Itabuna
• Hospital Brasilia — Brasília
• Hospital Sao Brasilia — Brasília
• Instituto de Cardiologia e Transplantes do Distrito Federal — Brasília
• Hospital de Messejana Dr. Carlos Alberto Studart Gomes — Goiânia
• … and 25 more centers

Canada · 25 centers

• Foothills Medical Centre — Calgary
• Grand Prairie Regional Hospital — Grande Prairie
• Nanaimo Regional General Hospital — Nanaimo
• Vancouver General Hospital — Vancouver
• Health Sciences Center Winnipeg — Winnipeg
• Grace General Hospital — Winnipeg
• St. Boniface General Hospital — Winnipeg
• Memorial University — St. John's
• … and 17 more centers

United States · 6 centers

• University of Chicago — Chicago
• Ochsner Clinic — Jefferson
• Maine Medical Centre — Portland
• Henry Ford Health System — Dearborn
• Cooper University Health Care — Camden
• Medical College of Wisconsin — Milwaukee

Publications

• ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berr PMID 34351721

Identifiers

NCT: NCT05848713 · ATTACC-CAP · OZM-129

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗