Heparin Anticoagulation in Septic Shock

Septic Shock Clinical Trial

— HALO  

Official title:

Heparin AnticoaguLation to Improve Outcomes in Septic Shock: The HALO International Phase II RCT

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03378466
• Other study ID #: HCA2017
• Status: Terminated
• Phase: Phase 2
• Start date: March 12, 2018
• Est. completion date: December 31, 2021

Study information

• Verified date: January 2021
• Source: University of Manitoba
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 178
• Est. completion date: December 31, 2021
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic
• Vasodilatory Shock

Intervention

Drug:
• Unfractionated heparin
UFH initiated at 18 IU/kg/hr, dosed according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin (aPTT) of 1.5 to 2.5 times that of the reference aPTT value or anti-Xa values targeted to local practice levels. Duration of study intervention will be a maximum of 5 days (120 hours) or until vasopressors have been discontinued for 24 continuous hours. All participants will then receive venous thromboprophylaxis according to local practice.

Other:
• Venous thromboprophylaxis (VTE)
May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings

Locations

Country	Name	City	State
Brazil	Hospital Sao Jose	Altamira
Brazil	Hospital Novo Atibaia	Atibaia
Brazil	Hospital de Amor (Barretos)	Barretos
Brazil	Santa Casa de Misericórdia de Belo Horizonte	Belo Horizonte
Brazil	Hospital Tacchini	Bento Gonçalves
Brazil	Hospital de Brasília	Brasilia
Brazil	Hospital Ortopedico e Medicina Especializada ltda. - HOME	Brasília
Brazil	Instituto de Cardiologia do Distrito Federal	Brasília
Brazil	Hospital Maternidade São José	Colatina
Brazil	Hospital Baía Sul	Florianópolis
Brazil	Hospital Nereu Ramos	Florianópolis
Brazil	Hospital de Amor Jales	Jales
Brazil	Unimed Cariri Hospital	Juazeiro Do Norte
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre
Brazil	Irmandade da Santa Casa de Misericordia de Porto Alegre	Porto Alegre
Brazil	Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto	Ribeirão Preto
Brazil	Hospital Bruno Born	Rio Grande
Brazil	Hospital da Cidade	Salvador
Brazil	Santa Casa de São João Del Rei	São João Del Rei
Brazil	Hospital AC Camargo	São Paulo
Brazil	Hospital Beneficência Portuguesa	São Paulo
Brazil	Hospital da Luz	São Paulo
Brazil	Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo	São Paulo
Brazil	Hospital e Maternidade Sao Vicente	São Paulo
Brazil	Hospital Santa Paula	São Paulo
Brazil	Hospital Sepaco	São Paulo
Brazil	Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo	São Paulo
Brazil	Universidade Federal de Sao Paulo - UNIFESP	São Paulo
Brazil	Hospital Ana Nery	Taguatinga
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Centre Hospitalier de l'Universite de Montreal (CHUM)	Montréal	Quebec
Canada	The Ottawa Hospital - Civic Campus	Ottawa	Ontario
Canada	The Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	Hopital de l'Enfant-Jesus	Quebec
Canada	Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval	Québec	Quebec
Canada	Niagara Health System - St Catharines Site	St. Catherines	Ontario
Canada	St Michael's Hospital	Toronto	Ontario
Canada	Vancouver Island Health Authority	Victoria	British Columbia
Canada	Health Sciences Centre Winnipeg	Winnipeg	Manitoba
Canada	St Boniface General Hospital	Winnipeg	Manitoba
Greece	ATTIKON University Hospital	Athens
Greece	Korgialeneion Benakeion Hospital	Athens
India	AMRI Hospital Kolkata	Kolkata
Pakistan	Dr Ruth K.M. PFAU Civil Hospital	Karachi
Pakistan	Shaheed Mohtarma Benazir Bhutto Trauma Center	Karachi
Pakistan	The Indus Hospital	Karachi
Pakistan	Mayo Hospital Lahore	Lahore
Philippines	The Asian Hospital	Manila
Philippines	The Medical City	Manila
Philippines	The Philippines General Hospital	Manila
United States	Froedtert Hospital	Milwaukee	Wisconsin

Sponsors (3)

Lead Sponsor	Collaborator
University of Manitoba	Canadian Institutes of Health Research (CIHR), CancerCare Manitoba

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Greece,  India,  Pakistan,  Philippines, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Vasopressor-free days.	The goal of phase II trial is to provide the international Data Safety Monitoring Committee (DSMC) with a sensible estimate to justify continued enrollment in an adaptive (sample size) trial. Vasopressor use, reflecting cardiovascular collapse due to overwhelming systematic inflammation, is a key inclusion criterion for the trial and durable discontinuation of such drugs and meaningful clinical improvement. Vasopressor-free days has been recommended as a preferred clinical outcome in phase II trials in critical illness.	30 days
Secondary	Clinical Outcome #1 - ICU mortality	Survival	From date of randomization until the first documentation of death from any cause or ICU discharge date or 90 days, whichever came first
Secondary	Clinical Outcome #2 - Hospital mortality	Survival	From date of randomization to the first documentation of death from any cause or hospital discharge date or 90 days, whichever came first.
Secondary	Clinical Outcome #3 - 90-day mortality	Survival	Up to day 90
Secondary	Clinical Outcome # 4 - ?SOFA score (Sequential Organ Failure Assessment)	Organ failure assessment using the SOFA scoring tool	Daily from randomization to ICU discharge or hospital discharge or time of death or to study day 9 if still in ICU or hospital.
Secondary	Clinical Outcome # 5 - Hospital-free days to day 90	Hospital admission duration in the context of survival	from hospital admission to hospital discharge or time of death to day 90
Secondary	Clinical Outcome #6 - Renal replacement therapy-free days to day 28	Renal replacement therapy duration in the context of survival	from start of renal replacement therapy to study day 28
Secondary	Safety Outcome #1 - Major Bleeding	Rates of major bleeding using a validated bleeding assessment tool	Assessed daily to day 8
Secondary	Safety Outcome #2 - Minor Bleeding	Rates of minor bleeding using a validated bleeding assessment tool	Assessed daily to day 8
Secondary	Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)	Incidence of any laboratory testing for HIT including screening or confirmatory tests	Assessed daily to day 8
Secondary	Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)	Postive confirmatory HIT test (one of Serotonin release assay (SRA) or Heparin induced platelet aggregation (HIPA))	Assessed daily to day 8
Secondary	Rate of enrolment	average number of patients enrolled per site per month	Monthly starting at individual site initiation through to end of enrollment, estimated two years