Background and significance: Sepsis and septic shock account for 10% of admissions to the intensive care unit and constitute the second most frequent cause of death among admitted patients. The mortality rate associated with septic shock ranges from 30% to 50% and death is often due to multiple organ dysfunction coupled with systemic inflammation. Given the pathobiological relationship between coagulation and inflammation in sepsis, treatment with anticoagulants has been investigated in this population. Multiple lines of evidence suggest that heparin, a widely available, inexpensive anticoagulant, may improve clinical outcomes in sepsis, but high quality evidence to guide practice is lacking.~Hypothesis: Intravenous (IV) unfractionated heparin (UFH) reduces mortality and morbidity when administered to patients with suspected septic shock.~Study Design: A pragmatic open-label international randomized trial comparing therapeutic dose intravenous unfractionated heparin (UFH) to standard care venous thromboprophylaxis in patients diagnosed with septic shock.~Setting: To increase the external validity/generalizability of the trial results, 20 sites in 4 countries will participate.~Study Population: Patients with systemic inflammation, vasopressor dependent shock, and signs of organ dysfunction.~Interventions: IV infusion of UFH at 18 IU/kg/hr, dosed according to total body weight and pragmatically adjusted according to usual care to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x that of the reference aPTT value (approximately 59-99 seconds). Alternately, therapeutic anti-Xa values (ie. values typically targeted for the treatment of venous thromboembolism) can be targeted based on local practice. Duration of heparin infusion is for a maximum of 5 days (120 hours) or until death, ICU discharge or discontinuation of vasopressors. The dose of UFH has been informed by our observational study and meta-analysis that showed a benefit of UFH in patients receiving therapeutic doses.~Control group: Local standard care for venous thromboprophylaxis (i.e. not therapeutic) which may include SC LMWH, SC UFH, sequential compression devices or graduated compression stockings.~Outcomes: At the end of the HALO international phase II trial, an international DSMB will be presented with by-group efficacy (vasopressor-free days) data in the context of 90-day mortality, and safety (bleeding and transfusion). With these data the DSMB will suggest: a) terminating enrollment for futility (lack of efficacy) or harm, or b) continuing to the phase III trial along with a recommended sample size to detect a clinically relevant difference in 90-day mortality. Patients will be analyzed according to the treatment group to which they are allocated. By-group data will remain blinded to study investigators so that these patients may be included in the HALO international phase III RCT. Our analytic approach provides a rationale to either stop, or to justify further investment in a large international phase III trial.
This study is a pragmatic open-label international randomized trial comparing therapeutic dose intravenous unfractionated heparin (UFH) to standard care venous thromboprophylaxis in patients diagnosed with septic shock.