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    Using Antifibrinolytics in Total Joint Arthroplasty

    Authors

    Joel A. Tucker, MD, and Mary I. O’Connor, MD

    Introduction

    In a number of clinical trials, antifibrinolytic medications used perioperatively have been shown to reduce blood loss and transfusion rates in a variety of surgical subspecialties [1-18]. 

    Background

    Antifibrinolytic drugs can decrease the need for blood transfusion following surgical procedures. Two such drugs are epsilon aminocaproic acid (EACA) and tranexamic acid (TA). Tranexamic acid has been studied more thoroughly in the orthopaedic literature and appears to be effective at decreasing blood loss and blood transfusion rates. 

    There has been some hesitancy in utilizing these medicines due to fear of adverse effects, primarily thromboembolic disease. 

    Mechanism and Pharmacokinetics

    EACA and TA are water soluble analogs of lysine; they block the lysine binding site of plasminogen and free plasmin [3,4]. This effectively displaces plasminogen from the fibrin surface, leading to inhibition of fibrinolysis [3,4]. 

    Following intravenous (IV) administration, maximum plasma levels of TA and EACA are reached in 5-15 minutes and diffuse rapidly in synovial fluid and membrane. The half-life of these drugs in plasma is 1-3 hours [3]. 

    TA and EACA are excreted by glomerular filtration non-metabolized in their active form. Thus, excretion is prolonged in patients with renal impairment [4]. The 24-hour urine recovery rate in EACA is 71% after a single IV bolus. 

    Animal studies have shown a serum concentration of 1,000 mcg/mL reduces fibrinolytic activity by 98%, 250 mcg/mL by 90%, and 100 mcg/mL by 80% [4]. EACA collects in soft tissues causing a continued inhibitory effect approximately 3 hours after its presence in the serum [4]. 

    TA and EACA are compared in Table 1.

    Table 1: Pharmacokinetics of TA and EACA

     

    TA

    EACA

    Half-life in plasma

    1-3 hours

    1-3 hours

    24-hour urine recovery rate after single IV bolus

    91 %

    71 %

    Plasma concentration yielding 80% fibrinolytic activity

    10 mgc/mL

    100 mcg/mL

    Continued inhibition after IV dosing

    8-12 hours

    3 hours

    TA= tranexamic Acid; EACA= epsilon aminocaproic acid

    Dosing and Efficacy

    The amount and frequency of dosing is variable in the literature. TA dosing ranges most frequently between 10-20 mg/kg; however, dosing as high as 150 mg/kg has been reported.  There does not yet appear to be a clear correlation between the dosage amount and clinical efficacy [5-18]. The frequency of the dose given is even more variable, with some studies giving a single IV injection preoperatively, others both pre- and postoperatively, and still others a bolus followed by a slow infusion. 

    The haemostatic effect of TA in arthroplasty patients has been investigated in many studies, with the majority showing a positive effect with higher postoperative hemoglobin levels and lower blood transfusion rates [5-18].

    A retrospective review of a single 20 mg/kg TA dose given either before incision in total hip arthroplasty or before tourniquet release in total knee arthroplasty showed a reduction in transfusion rates from 13.5% to 3.6% and 13.1% to 2.0%, respectively [19]. 

    In a randomized, prospective study by Johansson et al, 100 patients received either a single dose of 15 mg/kg or saline placebo before total hip arthroplasty, with average total blood loss of 0.97L in the TA group and 1.3L in the placebo group (p < 0.001) [11]. The rate of transfusion decreased from 40% in the placebo group to 20% in the TA group (p < 0.009). Postoperative drainage volume and drainage hemoglobin concentration were also significantly lower in the TA group.  According to the authors, this decrease in hemoglobin concentration in drainage makes drainage volume measurement alone inadequate to measure blood loss [11].

    A meta-analysis of 13 articles by Kagoma et al showed a 58% reduction in risk of transfusion with the use of antifibrinolytics in total hip arthroplasty [20].

    Limited studies have been conducted regarding the use of EACA in orthopedic surgery. In a prospective randomized study of 55 patients, Harley et al compared EACA to saline placebo in patients receiving total hip replacements [1]. They utilized a preoperative loading dose of 150 mg/kg followed by a 15 mg/kg/hr infusion for 5 hours. This dose schedule is similar to that used in cardiovascular procedures.

    Patients receiving EACA showed a 27% significant reduction in blood loss and an 11% reduction in transfusion rates, although this was not statistically significant, potentially due to the small size of the treatment groups [1]. There was no clinical evidence of thromboembolic disease in either group. 

    Not every study has shown antithrombolytics to reduce blood loss. A study by Good et al demonstrated no decrease in hidden blood loss in patients who received TA, but still did identify a significant decrease in blood transfusion rates when compared to a saline placebo group [21].

    Safety

    While most studies have indicated no increased incidence in symptomatic DVT or pulmonary embolus (PE) [1,7,10,22,23], a few studies have shown a non-statistically significant increased risk of DVT or PE [19,20].

    A meta-analysis of 27 studies reporting on venous thromboembolic (VTE) complications revealed no absolute change in risk between patients receiving antifibrinolytics versus those receiving placebo. The relative risk for patients receiving antifibrinolytics was 0.95, with a CI of 0.80 to 1.10. However, the authors cautioned that the strength of these conclusions is limited due to the lack of systematic investigation and small numbers of events

    Most studies excluded patients with a recent heart attack or stroke, patients with a history of VTE disease, and patients with a genetic predisposition to clotting disease.

    Recommendations

    Perioperative use of TA in total hip arthroplasty seems to be safe and effective at reducing blood loss and transfusions. A single 20-mg/kg dose just prior to incision or split to give a 10-mg/kg dose prior to incision and another dose 4 hours later appear to be reasonable approaches until further research on optimal dosing is performed. 

    Exclusion criteria may include patients with a recent heart attack or stroke, patients with a history of VTE disease, or patients with a genetic predisposition to clotting disease.

    More data on the use of EACA in total hip arthroplasty is needed until its efficacy can be determined.

    Author Information

    Joel A. Tucker, MD, specializes in general orthopaedics and adult reconstruction surgery with Bienville Orthopaedic Specialists in Mississippi. Mary I. O’Connor, MD, is Professor of Orthopaedic Surgery at Mayo Clinic, Jacksonville, Florida.

    Source

    Tucker JA, O’Connor MI. Antifibrinolytics in Total Hip Arthroplasty. OrthopaedicsOne Articles. In: OrthopaedicsOne – The Orthopaedic Knowledge Network. Created May 09, 2011 11:42. Last modified May 09, 2011 11:42 ver.2. Retrieved 2013-05-29, from http://www.orthopaedicsone.com/x/OQCuAw.

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