Clinical trial NCT03378466: Heparin Anticoagulation in Septic Shock
Official title: Heparin AnticoaguLation to Improve Outcomes in Septic Shock: The HALO International Phase II RCT
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Septic Shock
Vasodilatory Shock
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: CancerCare Manitoba
First posted: 2017-12-19
Enrollment: 178
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* ≥ 18 years of age
* Refractory hypotension documented within 18 hours prior to enrolment that requires the institution and ongoing use of vasopressor agents, (phenylephrine, norepinephrine, vasopressin, epinephrine, midodrine or dopamine \>5 mcg/kg/min) at the time of enrolment. Refractory hypotension is defined as a systolic blood pressure (SBP) less than 90 mm Hg, or a systolic blood pressure more than 30 mm Hg below baseline, or a mean arterial pressure (MAP) less than 65 mm Hg and receipt of ≥ 2 litres of intravenous fluid for the treatment of hypotension (≥ 1 litre if dialysis dependent end-stage renal disease or if the patient is felt to be in congestive heart failure).
* At least 1 other new organ dysfunction (in addition to refractory hypotension), defined by the following:

  1. Creatinine ≥1.5x the known baseline creatinine, or ≥ 26.5 µmol/L increase or \<0.5 mL/kg of urine output for 6-12 hours according to the KDIGO \[Kidney Disease improving Global Outcomes (KDiGO)\] guideline definition of acute kidney injury.
  2. Need for invasive mechanical ventilation or a P/F ratio \<250
  3. Platelets \<100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrolment
  4. Arterial pH \< 7.30 or base deficit \> 5 mmol/L in association with a lactate \> 4.0 mmol/L

Exclusion Criteria:

* Other forms of shock including cardiogenic, hemorrhagic, hypovolemic, neurogenic, or obstructive shock.
* Clinical suspicion or confirmation of a viral hemorrhagic shock syndrome including, but not limited to, dengue fever
* Rapid clinical improvement; vasopressors likely to be discontinued in the next 6 hours
* Received vasopressor therapy for greater than 18 hours prior to enrolment
* Bleeding Risk:

  1. Clinical: Active bleeding; head trauma; intracranial surgery or stroke within 3 months; history of intracerebral arteriovenous malformation, cerebral aneurysm or mass lesions of the central nervous system; history of a bleeding diatheses; gastrointestinal bleeding within 6 weeks; presence of an epidural or spinal catheter; selected cases of recent surgery where IV therapeutic UFH is considered contraindicated
  2. Laboratory: Platelet count \<50 x109/L, INR \>2.0, or baseline aPTT \>50 seconds prior to enrolment
* Known or suspected adverse reaction to UFH including heparin induced thrombocytopenia (HIT).
* Use of any of the following treatments: UFH to treat a thrombotic event within 12 hours before enrolment; LMWH at a higher dose than recommended for prophylactic use within 12 hours before the infusion; warfarin (if used within 7 days before study entry AND if the INR exceeds 2.0 at enrolment); thrombolytic therapy within 3 previous days; use of IIb/IIIa inhibitors within the previous 7 days.
* Need for therapeutic anticoagulation
* Terminal illness with a life expectancy of less than 3 months, or no commitment to aggressive care.
* Consent declined from patient or authorized 3rd party
* Physician refusal

Primary outcomes:
measure: Vasopressor-free days.
timeFrame: 30 days
Secondary outcomes:
measure: Clinical Outcome #1 - ICU mortality
timeFrame: From date of randomization until the first documentation of death from any cause or ICU discharge date or 90 days, whichever came first
measure: Clinical Outcome #2 - Hospital mortality
timeFrame: From date of randomization to the first documentation of death from any cause or hospital discharge date or 90 days, whichever came first.
measure: Clinical Outcome #3 - 90-day mortality
timeFrame: Up to day 90
measure: Clinical Outcome # 4 - ∆SOFA score (Sequential Organ Failure Assessment)
timeFrame: Daily from randomization to ICU discharge or hospital discharge or time of death or to study day 9 if still in ICU or hospital.
measure: Clinical Outcome # 5 - Hospital-free days to day 90
timeFrame: from hospital admission to hospital discharge or time of death to day 90
measure: Clinical Outcome #6 - Renal replacement therapy-free days to day 28
timeFrame: from start of renal replacement therapy to study day 28
measure: Safety Outcome #1 - Major Bleeding
timeFrame: Assessed daily to day 8
measure: Safety Outcome #2 - Minor Bleeding
timeFrame: Assessed daily to day 8
measure: Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)
timeFrame: Assessed daily to day 8
measure: Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)
timeFrame: Assessed daily to day 8
measure: Rate of enrolment
timeFrame: Monthly starting at individual site initiation through to end of enrollment, estimated two years
Other outcomes:
Locations:
city: Milwaukee
country: United States
facility: Froedtert Hospital
state: Wisconsin
city: Altamira
country: Brazil
facility: Hospital Sao Jose
city: Atibaia
country: Brazil
facility: Hospital Novo Atibaia
city: Barretos
country: Brazil
facility: Hospital de Amor (Barretos)
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericórdia de Belo Horizonte
city: Bento Gonçalves
country: Brazil
facility: Hospital Tacchini
city: Brasilia
country: Brazil
facility: Hospital de Brasília
city: Brasília
country: Brazil
facility: Hospital Ortopedico e Medicina Especializada ltda. - HOME
city: Brasília
country: Brazil
facility: Instituto de Cardiologia do Distrito Federal
city: Colatina
country: Brazil
facility: Hospital Maternidade São José
city: Florianópolis
country: Brazil
facility: Hospital Baía Sul
city: Florianópolis
country: Brazil
facility: Hospital Nereu Ramos
city: Jales
country: Brazil
facility: Hospital de Amor Jales
city: Juazeiro Do Norte
country: Brazil
facility: Unimed Cariri Hospital
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericordia de Porto Alegre
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto
city: Rio Grande
country: Brazil
facility: Hospital Bruno Born
city: Salvador
country: Brazil
facility: Hospital da Cidade
city: São João Del Rei
country: Brazil
facility: Santa Casa de São João Del Rei
city: São Paulo
country: Brazil
facility: Hospital AC Camargo
city: São Paulo
country: Brazil
facility: Hospital Beneficência Portuguesa
city: São Paulo
country: Brazil
facility: Hospital da Luz
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo
city: São Paulo
country: Brazil
facility: Hospital e Maternidade Sao Vicente
city: São Paulo
country: Brazil
facility: Hospital Santa Paula
city: São Paulo
country: Brazil
facility: Hospital Sepaco
city: São Paulo
country: Brazil
facility: Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo
city: São Paulo
country: Brazil
facility: Universidade Federal de Sao Paulo - UNIFESP
city: Taguatinga
country: Brazil
facility: Hospital Ana Nery
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Winnipeg
country: Canada
facility: St Boniface General Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: Health Sciences Centre Winnipeg
state: Manitoba
city: Ottawa
country: Canada
facility: The Ottawa Hospital - General Campus
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital - Civic Campus
state: Ontario
city: St. Catherines
country: Canada
facility: Niagara Health System - St Catharines Site
state: Ontario
city: Toronto
country: Canada
facility: St Michael's Hospital
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Universite de Montreal (CHUM)
state: Quebec
city: Québec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval
state: Quebec
city: Quebec
country: Canada
facility: Hopital de l'Enfant-Jesus
city: Athens
country: Greece
facility: ATTIKON University Hospital
city: Athens
country: Greece
facility: Korgialeneion Benakeion Hospital
city: Kolkata
country: India
facility: AMRI Hospital Kolkata
city: Karachi
country: Pakistan
facility: Dr Ruth K.M. PFAU Civil Hospital
city: Karachi
country: Pakistan
facility: Shaheed Mohtarma Benazir Bhutto Trauma Center
city: Karachi
country: Pakistan
facility: The Indus Hospital
city: Lahore
country: Pakistan
facility: Mayo Hospital Lahore
city: Manila
country: Philippines
facility: The Asian Hospital
city: Manila
country: Philippines
facility: The Medical City
city: Manila
country: Philippines
facility: The Philippines General Hospital
Study officials:
affiliation: University of Manitoba
name: Ryan Zarychanski, MD MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Anand Kumar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Ottawa
name: Dean A Fergusson, PhD MHA
role: PRINCIPAL_INVESTIGATOR
References: