Clinical trial NCT02261415: The HeLiX (Hemorrhage During Liver Resection: traneXamic Acid) Trial
Official title: The HeLiX (Hemorrhage During Liver Resection: traneXamic Acid) Trial: Tranexamic Acid (TXA) Versus Placebo to Reduce Perioperative Blood Transfusion in Patients Undergoing Liver Resection: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Cancer
Tumour
Surgery
Keywords: blood transfusion
blood loss
feasibility
outcome
liver resection
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: HepatoPancreaticoBiliary (HPB) Concept Team
First posted: 2014-10-10
Enrollment: 1386
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 is a Phase III multicentre randomized controlled trial (RCT) to evaluate the impact of tranexamic acid (TXA) on perioperative blood transfusion in patients undergoing liver resection. The rationale for this study includes: (1) experimental evidence supporting the use of TXA in other surgical populations; (2) lack of evidence in patients undergoing liver resection; (3) clinical uncertainty and extensive support amongst hepatobiliary surgeons, anaesthesiologists, and hematologists for this proposed trial; (4) a feasible and efficient study design; and (5) the importance of the question: incidence of blood transfusion in patients undergoing liver resection is high, and the consequences serious. The sample size for this study is 1230 participants.Participants enrolled in the prior Vanguard study will proceed directly into the RCT.

Detailed description: Purpose Compelling biological rationale and indirect evidence from other settings suggest that there is potential benefit to administering TXA to patients undergoing liver resection. A lack of consensus in the hepatobiliary community and lack of direct evidence in patients undergoing liver resection mandate a RCT.

Hypothesis To determine the impact of perioperative administration of TXA to patients undergoing liver resection on the need for blood transfusion and long-term survival.

Justification If TXA use in liver resection resulted in an important decrease in blood transfusions, clinical practice worldwide would be likely to change. Over 2000 patients in Canada undergo liver resection annually and could benefit from this simple, low-cost intervention. This intervention could easily be implemented in other countries, where many more patients undergo liver resection annually. Furthermore, TXA may be beneficial in other operative fields where bleeding is a major problem, including thoracic surgery, colorectal surgery, and many others.

Objectives

The primary outcome of the RCT will be:

1) Receipt of blood transfusion (% transfused): 7 days

The secondary outcomes of the RCT are:

1. Intraoperative blood loss will be assessed by adding the net weight of sponges and fluid suction (minus irrigation and intraoperative bile or other fluids in suction/sponge)
2. Total blood loss (postoperative day (POD)0 - POD7) will be assessed by Gross' formula, which uses the maximum postoperative decrease in the level of hemoglobin adjusted for the weight and height of the patient
3. Number of packed red blood cells (PRBC) units transfused (POD0 - POD7)
4. Postoperative incidence of symptomatic venous thromboembolic event confirmed with either computed tomography (CT) angiogram (for pulmonary embolism) or venous Doppler ultrasound (for deep venous thrombosis) (within 90 days of surgery)
5. Postoperative complications (within 90 days of surgery) will be determined using the Clavien-Dindo classification
6. Recurrence free survival (within 5 years of surgery) will be determined by review of patient medical record every 6 months until 5 years post-surgery

   a. Recurrence free survival is defined as the time from POD0 to the first event that is recurrent (local or distal) cancer or death (from any cause)
7. Overall survival (within 5 years of surgery) will be determined by review of patient medical record every 6 months until 5 years post-surgery

   a. Overall survival is defined as the time from date of POD0 to death from any cause
8. QOL will be determined by administering European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) -C30 and the QLQ- Liver Metastases Colorectal (LMC) 21 at baseline, 30 and 90 days following surgery
9. Perioperative mortality will be recorded between POD0 and POD7
10. Economic analysis will assess impact of TXA incorporation on health care resources and strategies for systematic utilization of TXA

Research Method This is a Phase III multicentre randomized controlled trial (RCT) to evaluate the impact of tranexamic acid (TXA) on perioperative blood transfusion in patients undergoing liver resection. The trial will conceal allocation, maximize possible blinding, independently assess the appropriateness of transfusion, use strategies to limit loss to follow-up and crossovers, and use a conservative stopping rule. Patients will be administered a single dose of study drug intravenously immediately after induction of anaesthesia, followed by infusion over eight hours.

Statistical Analysis Primary analysis will include only patients who underwent liver resection; patients who are randomized but do not receive liver resection (usually due to more advanced disease identified intraoperatively) will be excluded. A sensitivity analysis will be conducted whereby all randomized patients are included in the assessment of the primary outcome.

Eligibility criteria: Inclusion Criteria:

* Patient scheduled for open or laparoscopic liver surgery
* Age ≥18 years
* Cancer related diagnosis or indication (e.g. pre-cancer, suspicion of cancer, definite cancer)

Exclusion Criteria:

* Severe anemia (hemoglobin (Hgb) levels \<90 g/l)
* Documented arterial or venous thrombosis at screening or in past three months (not including therapeutic portal vein embolization)
* Anticoagulants (other than low-molecular-weight heparin (LMWH) or heparin in prophylactic doses to prevent deep vein thrombosis), direct thrombin inhibitors or thrombolytic therapy administered or completed within last week
* Known disseminated intravascular coagulation
* Severe renal insufficiency (creatinine clearance (CrCl) \<30 ml/min)
* History of seizure disorder
* Pregnant or lactating (a negative urine pregnancy test must be obtained for women of child bearing potential during the pretreatment evaluation)
* Acquired disturbance of colour vision
* Hypersensitivity to TXA or any of the ingredients
* Unable to receive blood products (i.e. difficulty with cross matching, refuses blood transfusion, or a past history of unexplained severe transfusion reaction)
* Previously enrolled in this study

Primary outcomes:
measure: Receipt of blood transfusion (% transfused): 7 days
timeFrame: 7 days
Secondary outcomes:
measure: Intraoperative blood loss
timeFrame: 7 days
measure: Total blood loss
timeFrame: 7 days
measure: Number of packed red blood cells (PRBC) units transfused
timeFrame: 7 days
measure: Postoperative incidence of symptomatic venous thromboembolic event
timeFrame: 90 days
measure: Postoperative complications assessed using Clavien-Dindo Grading System
timeFrame: 90 days
measure: Recurrence Free Survival (within 5 years of surgery)
timeFrame: 60 months
measure: Overall Survival (within 5 years of surgery)
timeFrame: 60 months
measure: Quality of Life (QOL) Assessment using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30
timeFrame: Baseline, 30 days, 90 days
measure: Quality of Life (QOL) Assessment using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Liver Module (LM)C21 Questionnaire
timeFrame: Baseline, 30 days, 90 days
measure: Perioperative mortality
timeFrame: 7 days
measure: Compare the cost of tranexamic acid (TXA) versus placebo on perioperative blood transfusion in patients undergoing liver resection
timeFrame: 90 days
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Kelowna
country: Canada
facility: Kelowna General Hospital
state: British Colombia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Health Research Institute
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Paul Karanicolas, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Karanicolas PJ, Lin Y, McCluskey S, Roke R, Tarshis J, Thorpe KE, Ball CG, Chaudhury P, Cleary SP, Dixon E, Eeson G, Moulton CA, Nanji S, Porter G, Ruo L, Skaro AI, Tsang M, Wei AC, Guyatt G; HepatoPancreaticoBiliary Community of Surgical ONcologists: Clinical, Evaluative, and Prospective Trials (HPB CONCEPT) Team. Tranexamic acid versus placebo to reduce perioperative blood transfusion in patients undergoing liver resection: protocol for the haemorrhage during liver resection tranexamic acid (HeLiX) randomised controlled trial. BMJ Open. 2022 Feb 24;12(2):e058850. doi: 10.1136/bmjopen-2021-058850.