Oral Tranexamic Acid vs. Oral Aminocaproic Acid to Reduce Blood Loss and Transfusion After Total Knee Replacement.
Condition: Knee Osteoarthritis; Blood Clot; Transfusion Related Complication; Blood Loss
MeSH terms: Thrombosis; Hemorrhage
Study type: Interventional
Phase: Phase 2

Summary: 
      This study compares two oral medications (tranexamic acid and aminocaproic acid) as
      hemostatic agent administered in patients undergoing total knee replacement.
    

Detailed description: 
      Background

      Total knee arthroplasty is the most common orthopedic procedure in knee surgery for the
      treatment of degenerative diseases such as OA and rheumatoid arthritis (RA), with nearly
      700,000 procedures performed in 2012 in the USA. The TKA frequently results in a significant
      loss of blood in a post-operative manner, which is estimated at more than 1500 ml (Hart et
      al., 2014). It has been reported that about 20 to 50% of patients under an TKA require a
      transfusion of allogenic blood. Even so, transfusion is associated with high costs, a high
      rate of hemolytic and non-hemolytic transfusion reactions, transmission of infectious
      diseases, high incidence of fluid overload and higher rates of post-operative morbidity and
      mortality. It has been reported in previous studies that the cost related to the transfusion
      of a single globular package reaches 1200 dollars (Bierbaum et al., 1999).

      Tranexamic acid (AXA) and aminocaproic acid (EACA) are synthetic drugs derived from Lysine
      that competitively inhibit the lysine receptors in the plasminogen and plasmin activating
      molecules, preventing the premature dissolution of the clot. These can be administered
      orally, intravenously or topically. Previous studies of systematic reviews have concluded
      that the topical and intravenous forms of tranexamic acid significantly decrease bleeding
      after an TKA (Churchill et al., 2016).

      Regarding the administration routes of the drugs in the intravenous form, cases of severe
      anaphylaxis and / or septic shock have been observed during its administration. The topical
      form carries the theoretical risk of increasing the rate of periprosthetic infections due to
      contamination of the needle and could cause sepsis. In the same way, the effects of topical
      application on the duration of the cement used in the prosthesis has not been determined in
      studies with long-term follow-up.

      There are 3 forms of presentation for the administration of tranexamic acid (oral, topical
      and intravenous), however the ideal route for its administration remains controversial. Yuan
      et al. (2017) conducted a study comparing the 3 routes of administration of tranexamic acid
      during the total replacement of the unilateral primary knee, finding that the three routes
      are effective in reducing blood loss and the rate of transfusion. In the same way, the oral
      route of administration proved to be equivalent or even more effective in the total
      replacement of the knee and hip to reduce blood loss. Similarly from a cost-benefit point of
      view it has also proven to be superior.

      Stabilizing the clot, antifibrinolytic drugs reduce perioperative blood loss and the need for
      transfusions. The use of AXA has recently become a popular strategy implemented by orthopedic
      surgeons in order to reduce blood loss and the rate of transfusions (Kim et al., 2014). An
      increase in postoperative bleeding has been described after the removal of the pneumatic
      tourniquet in the total knee replacement (TKR), which is attributed to the activation of the
      fibrinolytic system in the first hours after surgery (Jansen et al., 1999). This effect is
      positive by reducing the risk of a thromboembolic event associated with an orthopedic
      procedure, however it increases the risk of post-operative bleeding which increases the
      chances of requiring a transfusion (Spahn and Cassut, 2000).

      Medications that reduce hyperfibrinolysis can be administered to reduce blood loss (Spahn and
      Cassut, 2000). ATX and AAC are two drugs that can be used to prevent perioperative blood loss
      in TKR and other orthopedic procedures (Yamasaki et al., 2005, Bennett-Guerrero et al.,
      1997).

      The oral administration of antifibrinolytic drugs decreases the risk of developing
      anaphylaxis that occurs more frequently with the use of the intravenous route. For AXA it has
      been shown that both intravenous and oral routes are effective in reducing blood loss and the
      rate of transfusion.

      AAC is an effective antifibrinolytic when administered and is less expensive than the AXA so
      its use by oral route would reduce the risk of anaphylactic reactions in addition to reducing
      the cost of treatment. It has an average cost in its use of 2.70 dollars per surgical
      procedure in its intravenous form, compared to 40 dollars per surgery with the use of
      tranexamic acid in total hip replacement.

      At the moment there are no comparative studies of the efficacy of tranexamic acid and
      aminocaproic acid administered orally for the reduction of bleeding and transfusion index in
      patients undergoing total knee replacement.

      HYPOTHESIS

      There are no significant differences in blood loss, transfusion index and hemoglobin levels
      in patients undergoing total knee prostheses treated with tranexamic acid or aminocaproic
      acid orally.

      OBJETIVES

      General objective

      1. To compare the effect of oral aminocaproic acid as a hemostatic agent against oral
      tranexamic acid administered preoperatively and postoperatively in patients undergoing
      elective surgery of total knee replacement due to primary osteoarthrosis.

      Specific objectives

        1. Selection and randomization of patients.

        2. Performing total knee replacement surgery and administration of AAC or AXA according to
           randomization and the methodology established in this protocol

        3. Establishment of a protocol for the administration of aminocaproic acid orally for its
           use as a hemostatic agent in elective surgery of total knee replacement.

        4. Determination of blood loss, transfusion index, decrease in hemoglobin and hematocrit
           levels, drainage volume, intrahospital stay, analogous visual scale, SF-12 scale,
           thromboembolic complications and complications related to the wound between tranexamic
           acid and the aminocaproic acid, both orally, in each group in the pre, peri and
           post-operatively established times and compare them statistically.

        5. Determine and record the possible complications and side effects observed with the use
           of both drugs included in the study.

        6. Determine the cost and monetary savings associated with the administration of each drug.

        7. Comparison and statistical analysis of the results between the study groups.

      5.- METHODOLOGY

      Type of study: Controlled clinical trial.

      Study design: Experimental, longitudinal, comparative, prospective and blind.

      Approximate duration of the study: 18 months

      Type of population and sample size: A total of 80 patients undergoing elective surgery of
      total knee replacement due to unilateral primary gonarthrosis (40 patients per group) will be
      included.

      Investigation Site: Patients will be recruited from Consultation No. 15 of the Orthopedics
      and Traumatology Service of the University Hospital "Dr. José Eleuterio González "of the
      U.A.N.L. and the surgery will be carried out in the Surgical Therapeutics Department of the
      5th floor of the University Hospital of the U.A.N.L.

      Randomization mode: 80 sealed envelopes in which the group to which the patient belongs will
      be prepared prior to the start of the study. The patient will not know the group he will
      belong to until the moment of revealing the final results of the study.

      Recruitment Methodology: Each patient who is admitted for elective surgery of total knee
      replacement will be invited to participate voluntarily in the study. The principal
      investigator or one of the co-investigators will be responsible for thoroughly explaining the
      details of the study, including the potential benefits and risks thereof, as well as
      answering any doubts that may arise, if the patient agrees to participate they will be asked
      to sign the informed consent in the presence of two witnesses and a note will be made in the
      clinical file where their inclusion in the study will be registered, in the same way a copy
      of the consent will be given to the patient. For the purposes of the study, it will not be
      necessary to identify the patient, only their gender and age.

      The Head of the Anaesthesiology Service will be informed about the implementation of the
      protocol for the training in the management of the drugs to be administered in this protocol,
      to the nursing staff and residents of anesthesiology. The study population will be divided
      into 2 groups: 1. Tranexamic Acid Group and 2. Aminocaproic Acid Group with a total of 80
      patients (40 patients per group). The randomization process will be randomized by means of a
      statistical software.

      The surgeries of all the groups will be performed with the same surgical technique, using a
      total knee prosthesis model Vanguard, brand Biomet (Warsaw, IN), stabilized earlier. The
      patients will be operated by 3 subspecialists in joint knee surgery, professors of the
      Orthopedics and Traumatology Service of the University Hospital "Dr. José Eleuterio González
      "as the main surgeon and as surgical assistants, the resident physicians of Orthopedics and
      Traumatology who are rotating through the knee module or joint replacement.

      Surgical technique

      Previous epidural neuraxial block, prophylactic dose of antibiotic (Vancomycin 1 gr IV
      dissolved in 250 ml of 0.09% NaCl Physiological Solution to pass in two hours, administered
      150 minutes prior to the surgical procedure), using tourniquet at 100mmHg over the systolic
      pressure of the patient and previous protocol of asepsis and antisepsis (washing with 2%
      chlorhexidine the entire limb for 6 minutes and with duraprep® the area of the knee
      immediately prior to the initial incision) and placement of sterile fields. An insall type,
      medial parapatellar surgical approach will be performed and the conventional surgical
      technique will be followed for the placement of a two-compartment knee prosthesis.

      Subsequently, the wound will be closed by layers (capsule, subcutaneous cellular tissue and
      skin) in both groups. A 1/8 drenovack will be placed, fixed to the skin, which will be
      pinched for 1 hour and removed 48 hours after surgery. Thromboprophylaxis will be initiated
      with low molecular weight heparin 6 hours after the end of surgery. In the postoperative
      period, all patients with Hb levels of less than 8 mg / dl or with anemic syndrome clinical
      data will be transfused.

      Drug administration protocol:

      The sealed envelope will be opened on the preoperative day to identify which experimental
      group the patient belongs to and the oral administration of the medication will be included
      within the preoperative indications of the patient.

      Each patient will receive 3 doses of the drug to be evaluated according to the group to which
      it corresponds (1 preoperative dose and 2 postoperative doses). The protocol for the pre and
      post-operative administration of the drugs will be as follows:

      Medications: tranexamic acid (Lysteda, Pierre Fabre Mexico) or aminocaproic acid (Amikar,
      Wyeth), as appropriate, will be administered orally three times (administering 2 tablets each
      time). In the case of aminocaproinco tablets are 500 mg each and in the case of tranexamic
      acid are 650 mg each.

      The first administration will be two hours before the induction of anesthesia, the second 6
      hours post-surgery and the third 12 hours after surgery. All by oral administration with a
      drink of water. The medicines will be administered with a volume of 40 ml of water.

      For the aminocaproic acid, a total dose of 3 grams (6 tablets) divided between the 3
      administrations (1 gram each, ie 2 tablets of 500 mg) will be administered. For aminocaproic
      acid a total dose of 3.9 grams (6 tablets) divided between the 3 administrations (1.3 grams
      each, ie 2 tablets of 650 mg) will be administered.

      Parameters to be evaluated

      The general data of the patient will be obtained: age, gender, weight, height, body mass
      index and personal history, time of evolution of knee osteoarthritis and previous treatments,
      classification of osteoarthritis in the Kellgreen and Lawrence scale, femoro-tibial angle
      (APPENDIX 1). Pre-operative hemoglobin and hematocrit levels will be measured. As well as, at
      6 a.m. (24, 48 and 72 hours postsurgery). The expense for the drenovack will be measured /
      quantified at 6am (24 and 48 hours postsurgery). The transfusion rate will be measured,
      according to the level of hemoglobin described before. Finally the functional scales;
      Analogous visual scale (EVA); at 24, 48 and 72 hours and the SF-12 scale (ANNEX 2) (Vilalgut
      et al., 2005; Alonso et al., 1998; Ware et al., 1996; Gandek et al., 1998) in the
      preoperative day and in the 3rd postoperative day (hospital discharge).

      They will also obtain and analyze the amount of bleeding during surgery, the surgical time
      and peri and post-operative complications.

      Intrahospital follow-up

      Anticoagulation will be initiated with Heparin 5000 U.I subcutaneously 6 hours after the
      surgical procedure, and once in the hospitalization area the quantification of the drenovack
      expense will begin, a blood biometry and the administration of intravenous analgesia will be
      requested. On the day after the surgical procedure, the first surgical wound healing will be
      performed and the patient will start walking assisted by the doctor (this represents the
      normal post-operative management protocol of the patient undergoing a total knee replacement
      in our service).

      Patient's discharge

      It will be discharged by medical indication to the patient on the third post-operative day,
      if there is no type of contraindication, with indications of discharge in medical
      prescription and follow-up by the external consultation after two weeks.
    

Intervention name(s): Oral Tranexamic Acid; Oral Aminocaproic Acid
Intervention type(s): Drug; Drug
Intervention description(s): Patients undergoing total knee replacement who will receive three doses of tranexamic acid administered orally (1 prior to surgery and 2 subsequent to surgery).; Patients undergoing total knee replacement who will receive three doses of aminocaproic acid administered orally (1 prior to surgery and 2 subsequent to surgery).
Other intervention name(s): Amicar
Intervention MeSH terms: Tranexamic Acid; Aminocaproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Two study groups will be generated, each consisting of 40 research subjects, randomly each recipient will receive 3 doses of one of the two study drugs (tranexamic acid or aminocaproic acid). The group to which the patient belongs will be assigned through a computer program, the patient will not know to which group he belongs or what medication he will receive. The patients will be extracted from the external traumatology clinic.
Masking: Single (Participant)
Primary purpose: Prevention