Heparin Anticoagulation in Septic Shock

Phase 2

Terminated

• Conditions: Septic Shock; Vasodilatory Shock
• Interventions: Other: Venous thromboprophylaxis (VTE); Drug: Unfractionated heparin

• Registration Number: NCT03378466
• Lead Sponsor: University of Manitoba

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.

Study Timeline

• Study First Submitted: 2017-11-09
• Study First Submitted QC: 2017-12-18
• Study First Posted: 2017-12-19
• Study Start: 2018-03-12
• Status Verified: 2021-01
• Primary Completion: 2021-12-31
• Study Completion: 2021-12-31
• Last Update Submitted: 2022-05-17
• Last Update Posted: 2022-05-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 178

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Venous thromboprophylaxis (VTE)	Venous thromboprophylaxis (VTE)	as per local standard
Unfractionated Heparin (UFH)	Unfractionated heparin	UFH initiated at 18 IU/kg/hr

Primary Outcome Measures

Name	Time	Method
Vasopressor-free days.	30 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.

Secondary Outcome Measures

Name	Time	Method
Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)	Assessed daily to day 8	Incidence of any laboratory testing for HIT including screening or confirmatory tests
Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)	Assessed daily to day 8	Postive confirmatory HIT test (one of Serotonin release assay (SRA) or Heparin induced platelet aggregation (HIPA))
Clinical Outcome #6 - Renal replacement therapy-free days to day 28	from start of renal replacement therapy to study day 28	Renal replacement therapy duration in the context of survival
Clinical Outcome #2 - Hospital mortality	From date of randomization to the first documentation of death from any cause or hospital discharge date or 90 days, whichever came first.	Survival
Clinical Outcome # 4 - ∆SOFA score (Sequential Organ Failure Assessment)	Daily from randomization to ICU discharge or hospital discharge or time of death or to study day 9 if still in ICU or hospital.	Organ failure assessment using the SOFA scoring tool
Clinical Outcome # 5 - Hospital-free days to day 90	from hospital admission to hospital discharge or time of death to day 90	Hospital admission duration in the context of survival
Clinical Outcome #1 - ICU mortality	From date of randomization until the first documentation of death from any cause or ICU discharge date or 90 days, whichever came first	Survival
Clinical Outcome #3 - 90-day mortality	Up to day 90	Survival
Safety Outcome #1 - Major Bleeding	Assessed daily to day 8	Rates of major bleeding using a validated bleeding assessment tool
Safety Outcome #2 - Minor Bleeding	Assessed daily to day 8	Rates of minor bleeding using a validated bleeding assessment tool
Rate of enrolment	Monthly starting at individual site initiation through to end of enrollment, estimated two years	average number of patients enrolled per site per month

Trial Locations

Locations (51)

Hospital da Cidade; 🇧🇷 Salvador, Brazil

The Ottawa Hospital - Civic Campus; 🇨🇦 Ottawa, Ontario, Canada

Hospital Tacchini; 🇧🇷 Bento Gonçalves, Brazil

Instituto de Cardiologia do Distrito Federal; 🇧🇷 Brasília, Brazil

Hospital de Amor Jales; 🇧🇷 Jales, Brazil

Irmandade da Santa Casa de Misericordia de Porto Alegre; 🇧🇷 Porto Alegre, Brazil

Hospital Nereu Ramos; 🇧🇷 Florianópolis, Brazil

Hospital da Luz; 🇧🇷 São Paulo, Brazil

Hospital Novo Atibaia; 🇧🇷 Atibaia, Brazil

Hospital de Amor (Barretos); 🇧🇷 Barretos, Brazil

Hospital AC Camargo; 🇧🇷 São Paulo, Brazil

Hospital e Maternidade Sao Vicente; 🇧🇷 São Paulo, Brazil

Hospital das Clinicas da faculdade de Medicina de Universidade de São Paulo; 🇧🇷 São Paulo, Brazil

Hospital Santa Paula; 🇧🇷 São Paulo, Brazil

The Ottawa Hospital - General Campus; 🇨🇦 Ottawa, Ontario, Canada

Instituto de Assistência Médica ao Servidor Público Estadual de São Paulo; 🇧🇷 São Paulo, Brazil

Universidade Federal de Sao Paulo - UNIFESP; 🇧🇷 São Paulo, Brazil

Hospital Beneficência Portuguesa; 🇧🇷 São Paulo, Brazil

Vancouver Island Health Authority; 🇨🇦 Victoria, British Columbia, Canada

ATTIKON University Hospital; 🇬🇷 Athens, Greece

Hopital de l'Enfant-Jesus; 🇨🇦 Quebec, Canada

St Michael's Hospital; 🇨🇦 Toronto, Ontario, Canada

Health Sciences Centre Winnipeg; 🇨🇦 Winnipeg, Manitoba, Canada

St Boniface General Hospital; 🇨🇦 Winnipeg, Manitoba, Canada

AMRI Hospital Kolkata; 🇮🇳 Kolkata, India

The Indus Hospital; 🇵🇰 Karachi, Pakistan

Mayo Hospital Lahore; 🇵🇰 Lahore, Pakistan

Foothills Medical Centre; 🇨🇦 Calgary, Alberta, Canada

Centre Hospitalier de l'Universite de Montreal (CHUM); 🇨🇦 Montréal, Quebec, Canada

Institut Universitaire de Cardiologie et de Pneumologie de Quebec - Universite Laval; 🇨🇦 Québec, Quebec, Canada

The Medical City; 🇵🇭 Manila, Philippines

Froedtert Hospital; 🇺🇸 Milwaukee, Wisconsin, United States

Dr Ruth K.M. PFAU Civil Hospital; 🇵🇰 Karachi, Pakistan

Korgialeneion Benakeion Hospital; 🇬🇷 Athens, Greece

Shaheed Mohtarma Benazir Bhutto Trauma Center; 🇵🇰 Karachi, Pakistan

The Philippines General Hospital; 🇵🇭 Manila, Philippines

The Asian Hospital; 🇵🇭 Manila, Philippines

Santa Casa de Misericórdia de Belo Horizonte; 🇧🇷 Belo Horizonte, Brazil

Hospital de Brasília; 🇧🇷 Brasilia, Brazil

Hospital Ortopedico e Medicina Especializada ltda. - HOME; 🇧🇷 Brasília, Brazil

Hospital Maternidade São José; 🇧🇷 Colatina, Brazil

Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto; 🇧🇷 Ribeirão Preto, Brazil

Unimed Cariri Hospital; 🇧🇷 Juazeiro Do Norte, Brazil

Hospital de Clínicas de Porto Alegre; 🇧🇷 Porto Alegre, Brazil

Hospital Sepaco; 🇧🇷 São Paulo, Brazil

Hospital Bruno Born; 🇧🇷 Rio Grande, Brazil

Santa Casa de São João Del Rei; 🇧🇷 São João Del Rei, Brazil

Hospital Ana Nery; 🇧🇷 Taguatinga, Brazil

Hospital Baía Sul; 🇧🇷 Florianópolis, Brazil

Niagara Health System - St Catharines Site; 🇨🇦 St. Catherines, Ontario, Canada

Hospital Sao Jose; 🇧🇷 Altamira, Brazil