Tranexamic Acid (TXA) Versus Epsilon Aminocaproic Acid (EACA) Versus Placebo for Spine Surgery
Condition: Scoliosis
MeSH terms: Scoliosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) have been reported to reduce blood
      loss in the cardiac surgery literature but they have not been reported in use head-to-head in
      the orthopedic surgery literature. In a randomized, double-blind, prospective study we
      believe that TXA will be more effective than both EACA and placebo at reducing blood loss for
      corrective spinal surgery.
    

Detailed description: 
      Study Design The study is designed as a prospective, randomized, double-blinded control
      trial. The patient, researcher, surgeon, and anesthesiologist will all be blinded to the
      patient's treatment. Patients will either receive TXA, EACA, or normal saline. The study will
      determine and compare differences in blood loss intra-operatively and estimate blood loss
      postoperatively through monitoring of subfascial Hemovac drain outputs at the incision site
      between the three groups. Postoperatively, laboratory values, drain outputs, and clinical
      outcomes will be carefully followed.

      The primary goal of this study is to compare the efficacy of TXA to EACA to placebo in
      patients undergoing corrective spinal surgery for adolescent idiopathic scoliosis (AIS),
      neuromuscular scoliosis (NMS), and with adult deformity (AD). Outcome measures will include
      intra-operative and perioperative blood loss, transfusion rates, complete blood counts, and
      coagulation profiles, as well as postoperative wound drainage, complications, and length of
      stay.

      Standardized treatment protocol For EACA, the loading dose is 100mg/kg infused over 15
      minutes, while the maintenance dose is 10mg/kg hr. For TXA, the loading dose is 10mg/kg
      infused over 15 minutes, while the maintenance dose is 1/mg/kg hr. Since TXA is prepared by
      pharmacy at a concentration ten times less than the concentration of EACA, the volume of
      medication administered during the loading and maintenance phase is identical. This is the
      ideal method for physician blinding and has been discussed in depth with the anesthesia
      department. The dosing regimen is also in accordance with existing guidelines and current
      literature. The literature also reports safely using TXA at a 100mg/kg loading dose followed
      by a 10mg/kg hr maintenance dose. However, improved efficacy at this higher dose of TXA has
      not been proven in a single orthopedic study. Since TXA is reported to be ten times more
      potent than EACA, delivering a dose of TXA that is ten times smaller than EACA is valid and
      well supported in the literature.

      Surgical correction of the spine Dorsal lumbar access is achieved by a posterior lumbar skin
      incision along the midline. Paravertebral muscles are dissected away from bony structures
      taking care to achieve adequate hemostasis. Multi-level spinal osteotomies and/or releases of
      bony and ligamentous structures are performed to increase mobility of the spinal column. Bone
      grafts consisting of autologous bone or allograft are filled in to allow for bony fusion of
      the spinal column and limit motion. Pedicle screws are placed segmentally into vertebral
      bodies to provide adequate fixation of rod instrumentation. Stainless steel, titanium, or
      cobalt rods are placed to help correct and stabilize the spine while fusion occurs. Generally
      the greatest blood loss occurs during dissection and placement of pedicle screws while rod
      placement is associated with less blood loss. Subfascial Hemovac or Jackson-Pratt drains are
      placed at the wound site during closure to allow for adequate drainage and determination of
      post-operative blood loss.

      Investigation schedule and follow-up Data will be collected pre-operatively regarding
      individual patient demographics, laboratory values, and the surgical procedure to be
      performed. Intra-operatively, data will be gathered to estimate blood loss and account for
      changes in fluid balance. Anesthesiologists are asked to maintain a MAP of 60 during the
      surgical exposure and anchor placement and a MAP of 70-90 during the surgical correction.
      Similarly, surgeons are asked to place only subfascial Hemovac drains at the incision site.
      These are both standard practice and have . Postoperatively, laboratory values, drain output,
      and clinical outcomes are carefully followed until the patient is discharged. Given the
      increased risk of renal failure with the use of Aprotinin changes in BUN to CR ratio are
      carefully monitored post-operatively. This data is recorded onto a de-identified data
      collection sheet by the researchers. These patient data sheets are then entered onto a
      protected electronic database, while the data sheets are stored as a back-up until the study
      is complete. Once the completed database is analyzed and summarized, the results will be
      presented to the involved participants without any identifiable patient information.

      Statistical considerations While useful, this analysis is limited by the great variability in
      study design and control groups between prior orthopedic studies. Since no orthopedic study
      has compared TXA and EACA together, conducting a power analysis required pooling of data from
      two or three studies. This proved difficult, as control groups were dissimilar between the
      studies.

      Power analysis was performed multiple times using data from several studies. When estimating
      the sample size required comparing TXA and EACA, attempts were made to choose two studies
      with similar intra-operative blood losses within the control groups. A cardiac study, albeit
      with dissimilar sample variance, was also used to estimate the sample size needed for this
      study. Finally, determining the sample size for outcomes of total blood loss and transfusion
      requirements proved difficult as even fewer studies reported these outcomes. Blood loss will
      be estimated in the operation room, but will also be calculated taking into account patient
      body mass, pre/postoperative hematocrit, and relative fluid balance. This will minimize the
      variance in reported blood loss. A power analysis will be performed again once 60 patients
      with AIS, NMS, or AD have been enrolled into the study.

      With a single institution of surgeons and anesthesiologists participating in the study, we
      expect a smaller variation in operative blood loss than reported in prior studies. Data will
      not only be analyzed for all patients collectively, but will also be stratified by diagnosis
      (AIS, NMS, and AD). The purpose of stratifying into these groups is threefold. First,
      separation by diagnosis allows for more diligent control of patient-related factors that may
      affect blood loss and transfusion rate. Secondarily, stratification by diagnosis allows for a
      better understanding of which patients benefit most from one treatment option over another.
      Lastly, it allows for a broader application of the results from this study not only to
      patients with AIS, but to all spinal deformity patients.

      An analysis of variance, univariate, and multivariate logistic regression analysis will be
      used to analyze the difference in outcomes. Odds ratios will be calculated regarding the risk
      for autologous or allogenic transfusion both intra and postoperatively. P-values will be
      calculated regarding the relative blood loss in the intra and postoperative periods as well.
      The groups will be analyzed to characterize the homogeneity of their pre-operative
      characteristics that may influence blood loss. Patients with AIS, NMS or AD will be
      stratified by primary diagnosis and analyzed separately but also collectively accounting for
      patient and surgery-related confounders. Non-continuous data will be analyzed with a
      non-parametric test. Pre-operative curve characteristics including Cobb angle and number of
      vertebrae fused will be categorized to ensure similar groups for comparison.
    

Intervention name(s): Tranexamic Acid; Normal Saline; Epsilon aminocaproic acid
Intervention type(s): Drug; Drug; Drug
Intervention description(s): For TXA, the loading dose is 10mg/kg infused over 15 minutes, while the maintenance dose is 1/mg/kg hr.; Normal saline of same volume as the intervention group will be given as the intervention group as a loading dose and maintenance dose.; For EACA, the loading dose is 100mg/kg infused over 15 minutes, while the maintenance dose is 10mg/kg hr.
Other intervention name(s): TXA; Placebo; Amicar, EACA
Intervention MeSH terms: Tranexamic Acid; Aminocaproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: antifibrinolytics