Heparin AnticoaguLation to Improve Outcomes in Septic Shock: The HALO International Phase II RCT
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 178
- 试验地点
- 51
- 主要终点
- Vasopressor-free days.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •≥ 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:
- •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.
- •Need for invasive mechanical ventilation or a P/F ratio <250
- •Platelets <100 x109/L, or a drop of 50 x109/L in the 3 days prior to enrolment
- •Arterial pH < 7.30 or base deficit > 5 mmol/L in association with a lactate > 4.0 mmol/L
排除标准
- •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:
- •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
- •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
研究组 & 干预措施
Unfractionated Heparin (UFH)
UFH initiated at 18 IU/kg/hr
干预措施: Unfractionated heparin (Drug)
Venous thromboprophylaxis (VTE)
as per local standard
干预措施: Venous thromboprophylaxis (VTE) (Other)
结局指标
主要结局
Vasopressor-free days.
时间窗: 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.
次要结局
- Safety Outcome #3 - Suspected HIT (Heparin induced thrombocytopenia)(Assessed daily to day 8)
- Safety Outcome #4 - Confirmed HIT (Heparin induced thrombocytopenia)(Assessed daily to day 8)
- Clinical Outcome #6 - Renal replacement therapy-free days to day 28(from start of renal replacement therapy to study day 28)
- 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.)
- 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.)
- Clinical Outcome # 5 - Hospital-free days to day 90(from hospital admission to hospital discharge or time of death to day 90)
- 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)
- Clinical Outcome #3 - 90-day mortality(Up to day 90)
- Safety Outcome #1 - Major Bleeding(Assessed daily to day 8)
- Safety Outcome #2 - Minor Bleeding(Assessed daily to day 8)
- Rate of enrolment(Monthly starting at individual site initiation through to end of enrollment, estimated two years)