Heparin Anticoagulation in Septic Shock

NCT ID: NCT03378466

Last Updated: 2022-05-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 178 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-03-12
• Study Completion Date: 2021-12-31

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.

Conditions

Septic Shock; Vasodilatory Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Unfractionated Heparin (UFH)

UFH initiated at 18 IU/kg/hr

Group Type: EXPERIMENTAL

Unfractionated heparin

Intervention Type: DRUG

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.

Venous thromboprophylaxis (VTE)

as per local standard

Group Type: OTHER

Venous thromboprophylaxis (VTE)

Intervention Type: OTHER

May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings

Interventions

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.

Intervention Type: DRUG

Venous thromboprophylaxis (VTE)

May include subcutaneous heparin or dalteparin, sequential compression device or graduated compression stockings

Intervention Type: OTHER

Other Intervention Names

Heparin

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

CancerCare Manitoba

OTHER

Sponsor Role: collaborator

University of Manitoba

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Ryan Zarychanski, MD MSc

Role: PRINCIPAL_INVESTIGATOR

University of Manitoba

Anand Kumar, MD

Role: PRINCIPAL_INVESTIGATOR

University of Manitoba

Dean A Fergusson, PhD MHA

Role: PRINCIPAL_INVESTIGATOR

University of Ottawa

Locations

St Michael's Hospital

Toronto, Ontario, Canada

Centre Hospitalier de l'Universite de Montreal (CHUM)

Montreal, Quebec, Canada

Froedtert Hospital

Milwaukee, Wisconsin, United States

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

Brasília, , 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, , Brazil

Foothills Medical Centre

Calgary, Alberta, Canada

Vancouver Island Health Authority

Victoria, British Columbia, Canada

St Boniface General Hospital

Winnipeg, Manitoba, Canada

Health Sciences Centre Winnipeg

Winnipeg, Manitoba, Canada

The Ottawa Hospital - General Campus

Ottawa, Ontario, Canada

The Ottawa Hospital - Civic Campus

Ottawa, Ontario, Canada

Niagara Health System - St Catharines Site

Saint Catherines, Ontario, Canada

Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval

Québec, Quebec, Canada

Hopital de l'Enfant-Jesus

Québec, , Canada

ATTIKON University Hospital

Athens, , Greece

Korgialeneion Benakeion Hospital

Athens, , Greece

AMRI Hospital Kolkata

Kolkata, , India

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, , Pakistan

The Asian Hospital

Manila, , Philippines

The Medical City

Manila, , Philippines

The Philippines General Hospital

Manila, , Philippines

Countries

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

Other Identifiers

HCA2017

Identifier Type: -

Identifier Source: org_study_id