Clinical trial NCT02911831: IV Tranexamic Acid Prior to Hysterectomy
Official title: IV Tranexamic Acid Prior to Hysterectomy for Reduction of Intraoperative Blood Loss: A Randomized Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Hysterectomy
Blood Loss, Surgical
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2016-09-22
Enrollment: 71
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The objective of this study is to determine the effect of 1g of IV tranexamic acid given within 1 hour pre-operatively on intraoperative blood loss at time of hysterectomy.

Detailed description: Tranexamic acid (TXA) is a synthetic lysine analog that inhibits plasmin fibrinolysis. It may be administered orally, intravenously, or topically, with a rapid onset of action (tmax = appx 3 hours) and 11-hour half-life. It is 6 to 10 times more potent than aminocaproic acid, another commonly used synthetic antifibrinolytic agent. Typical IV dosing is 10 mg/kg followed by infusion of 1mg/kg/hour, or simply 1g intravenously in one dose.

The efficacy of tranexamic acid in control of hemorrhage in trauma patients has been reported extensively. The CRASH-2 trial collaborators randomized 20,211 adult trauma patients with significant bleeding or at risk of significant bleeding within 8 hours of injury to IV tranexamic acid or placebo. All-cause mortality was significantly reduced with tranexamic acid (RR .91; p = .0035). Additionally, risk of death due to bleeding was significantly lower in those receiving tranexamic acid (RR .85; p = .0077). No differences in risk of vascular occlusive events were noted. Further analysis revealed reduced risk of death from bleeding if TXA was given within 3 hours of injury; treatment administered after 3 hours from injury increased the risk of death due to bleeding.

Administration of TXA during elective surgery has also been investigated. A 2011 systematic review of 252 randomized trials of patients undergoing elective surgery across disciplines included administration of TXA, aminocaproic acid, and aprotinin. TXA administration reduced the risk of transfusion peri-operatively (RR .61). A 2012 meta-analysis of TXA use in both elective an emergency surgery revealed that TXA reduced the risk of transfusion by one-third. The effect of TXA on risk of myocardial infarction, deep vein thrombosis, and pulmonary embolism was not statistically significant.

The utility of TXA appears to extend to obstetric hemorrhage. Several published studies exist analyzing its use in prevention of postpartum hemorrhage, though the drug is not considered standard for prevention or treatment of this condition. A pilot randomized open-label trial of IV TXA in women with postpartum hemorrhage over 800cc reported a lower median blood loss between groups, though the effect was modest. Additionally, significantly fewer women in the TXA group required transfusion or invasive procedures. A recent Cochrane review reports on twelve trials of low risk women undergoing cesarean section or spontaneous birth who received uterotonics with or without the addition of TXA. TXA was effective in decreasing estimated blood loss over 1 liter in women undergoing cesarean section. Mean blood loss was significantly lower in women receiving TXA (mean difference -77.79mL); effect was similar for women undergoing cesarean section and vaginal birth. Finally, the WOMAN trial is a large, ongoing, placebo-controlled trial examining the effect of early TXA administration in clinically diagnosed postpartum hemorrhage.

The use of TXA in the management of acute and abnormal uterine bleeding has been reported, and is FDA-approved for treatment of menorrhagia. One randomized study of oral TXA in the treatment of ovulatory menorrhagia reported a 45% decrease in mean menstrual blood loss with use of TXA as compared with placebo. Other studies have echoed these findings, with TXA more effective than NSAIDs but less effective than the levonorgestrel intrauterine device (IUD) in decreasing menstrual blood loss. More recently, a double-blind, placebo-controlled randomized-controlled trial (RCT) confirmed a significant decrease in menstrual blood loss(mean -69cc), improvements in social/physical limitations caused by menorrhagia and self-perceived menstrual blood loss. No data exist examining the efficacy of IV TXA in the management of acute or severe uterine bleeding.

Few studies have specifically examined the utility of prophylactic TXA in reducing mean blood loss during hysterectomy or other gynecologic procedures. In one study of patients undergoing endometrial ablation and endoscopic endometrial resection, intraoperative and postoperative IV TXA significantly decreased total blood loss. In patients undergoing major debulking surgery for gynecologic cancers, administration of IV TXA has been shown to decrease intra-operative blood loss by 30%. One well-designed study of women with advanced-stage ovarian cancer randomized patients to 15 mg/kg IV TXA or the same volume of placebo immediately before surgery. Outcomes included significantly lower mean estimated blood loss and decreased need for transfusion in the TXA group.

This study sought to determine whether a single preoperative dose of IV tranexamic acid effectively reduces intraoperative blood loss and need for transfusion in patients undergoing laparoscopic, abdominal, or vaginal hysterectomy for benign indications.

Objective:

To determine the effect of 1g of IV tranexamic acid given within 1 hour pre-operatively on intraoperative blood loss at time of hysterectomy.

Primary endpoint:

Estimated blood loss as determined by anesthesia and surgeon at time of hysterectomy, difference between post-operative and pre-operative hemoglobin, length of hospital stay, length of procedure, need for blood transfusion and post-operative venous thromboembolic events.

Treatment Dosage and Administration:

1g IV tranexamic acid or 100ml 0.9% sodium chloride solution administered within 1 hour of the start of the procedure

Eligibility criteria: Inclusion Criteria:

1. Patients presenting for hysterectomy for any benign indication including but not limited to abnormal uterine bleeding, menorrhagia, uterine fibroids, adenomyosis, pelvic pain, dysmenorrhea, pelvic organ prolapse or endometriosis.
2. Age ≥ 18 years
3. Pre-operative hemoglobin \>8 g/dl
4. Willing to have IV tranexamic acid or a placebo prior to hysterectomy
5. Ability to understand and the willingness to sign a written informed consent.
6. Can be previously treated with Depo-Lupron, Depo-Provera, Oral Contraceptive pills, Mirena IUD, endometrial ablation, myomectomy, oral progestins
7. Hysterectomy in combination with the following procedures is permitted: unilateral/bilateral salpingectomy or oophorectomy, ovarian cystectomy, fulguration/excision of endometriosis, appendectomy, sacrocolpopexy, anterior/posterior repair, uterosacral vault suspension, retropubic midurethral sling and cystoscopy

Exclusion Criteria:

1. Patients with known or suspected endometrial/ovarian/cervical cancer.
2. Patients undergoing hysterectomy for endometrial hyperplasia or cervical dysplasia.
3. Patients currently undergoing treatment for any type of cancer.
4. Patients with known bleeding/clotting disorders or a history of thromboembolism (including deep venous thrombosis or pulmonary embolism)
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tranexamic acid.
6. Any procedures which occur in combination with other elective surgical procedures (such as abdominoplasty, breast augmentation, etc) which are not included in the previously mentioned inclusion criteria above will be excluded from data analysis.
7. Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, subarachnoid hemorrhage, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
8. Patients with acquired defective color vision
9. Patients with known renal failure and/or Cr \> 5 within the last 6 months

Primary outcomes:
measure: Intra-operative blood loss
timeFrame: Intra-operative
Secondary outcomes:
measure: Change in hemoglobin, postoperative from baseline
timeFrame: < 12 hours
measure: Need for blood transfusion
timeFrame: Intra-operative
measure: Length of hospital stay
timeFrame: <1 week
measure: Length of operative procedure
timeFrame: <12 hours
measure: Rates of postoperative thromboembolic events
timeFrame: 12 weeks
measure: Incidence of drug-related adverse events
timeFrame: 12 weeks
measure: Health care cost
timeFrame: 12 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University - Northwestern Medicine, Lavin Family Pavillion
state: Illinois
Study officials:
affiliation: Northwestern University, Northwestern Memorial Hopsital
name: Magdy Milad, MD
role: PRINCIPAL_INVESTIGATOR
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