Elsevier

Thrombosis Research

Volume 123, Issue 5, March 2009, Pages 687-696
Thrombosis Research

Review Article
Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: A systematic review of randomized trials

https://doi.org/10.1016/j.thromres.2008.09.015Get rights and content

Abstract

Background

Minimizing bleeding and transfusion is desirable given its cost, complexity and potential for adverse events. Concerns have been heightened by recent data demonstrating that bleeding events may predict worse outcomes and by warnings about the safety of erythropoietic stimulating agents. Prior small studies suggest that antifibrinolytic agents may reduce bleeding and transfusion need in patients undergoing total hip replacement (THR) or total knee arthroplasty (TKA). However, no single study has been large enough to definitively determine if these agents are safe and effective. To address this issue we performed a systematic review of randomized trials describing the use of tranexamic acid, epsilon aminocaproic acid, or aprotinin administration in the perioperative setting.

Methods

MEDLINE, EMBASE, CINAHL and the Cochrane databases were searched for relevant trials. Two independent reviewers abstracted total blood loss, transfusion requirements, and venous thromboembolism (VTE) rates. Data were combined using the Mantel-Haenszel method and dichotomous data expressed as relative risk (RR) with 95% confidence intervals (CI).

Results

Patients receiving antifibrinolytic agents had reduced transfusion need (RR 0.52; 95% CI, 0.42 to 0.64; P < 0.00001), reduced blood loss and no increase in the risk of VTE (RR 0.95% CI, 0.80 to 1.10, I2 = 0%, P = 0.531).

Conclusions

We conclude that antifibrinolytic agents may reduce bleeding and transfusion in patients undergoing THR or TKA who receive appropriate antithrombotic prophylaxis. There is a need for a large, adequately powered prospective study to carefully examine the safety and efficacy of these agents.

Introduction

In 2004, over 480,000 total knee arthroplasties (TKA) and over 230,000 total hip replacements (THR) were performed in the United States [1]. About half of patients undergoing THR and TKA require transfusion with an average transfusion requirement of 2.0 units [2] and total average blood loss of 1,500 mL [3]. TKA generally has lower intra-operative losses due to tourniquet use but is complicated by higher hidden blood loss [4]. Despite blood-sparing techniques such as cell salvage, normovolemic hemodilution, and surgical hemostasis techniques, bleeding requiring transfusion is still frequently encountered peri- and post-operatively. This need for transfusion is concerning as increasing data suggests that both bleeding and resultant transfusions are associated with an increased risk for adverse outcomes. Among patients with acute coronary syndromes, patients who undergo transfusion have increased rates of death and myocardial infarction, even after adjustment for important confounding factors [5], [6].

Furthermore, alternatives to transfusion including the use of erythropoietic stimulating agents (ESAs) may also be associated with an increased risk of adverse outcomes. ESAs are used to facilitate the ability for patients to donate autologous blood units for transfusion and to hasten the recovery of the hemoglobin level after surgery. Although effective in raising the hemoglobin level, these agents are expensive and have recently been shown to increase the risk for deep vein thrombosis in patients undergoing orthopedic surgery [7]. Routine use of these agents as a method to reduce transfusion is consequently problematic; the frequency with which they are actually used in patients undergoing major orthopedic surgery is, to our knowledge, unknown.

Antifibrinolytic agents such as tranexamic acid (TXA), epsilon aminocaproic acid (EACA) and aprotinin are widely available agents which enhance hemostasis, thus potentially reducing blood loss and the need for transfusion. EACA and TXA are synthetic amino acid derivatives which bind reversibly to plasminogen, inhibiting binding to fibrin and activation to plasmin [8], [9]. Aprotinin, a bovine lung tissue extract, is a naturally occurring polypeptide protease inhibitor that binds and inhibits plasmin [10]. However, like ESAs, these agents may also increase the risk of venous thromboembolism (VTE), as was demonstrated in cardiac surgery patients receiving aprotinin [11], [12].

Currently, although extensively studied in cardiovascular and vascular surgery[5], [6] there is a lack of data examining the efficacy and safety of these agents in other surgical settings. Despite these limitations, a recent meta-analysis [13] suggests that intravenous antifibrinolytic agents are effective in reducing transfusion requirements in patients undergoing various types of orthopaedic surgery. We performed a systematic review and meta-analysis of randomized trials to assess whether antifibrinolytic agents (TXA, EACA, aprotinin) reduce bleeding and transfusion requirements in patients undergoing joint replacement, as well as their effect on the rate of VTE.

Section snippets

Search Methodology

We sought published randomized trials that evaluated TXA, EACA, or aprotinin in patients undergoing THR or TKA. A comprehensive search strategy was developed in consultation with a professional librarian. The search was limited to papers and abstracts written in English. The electronic databases searched were: MEDLINE (1966 to May Week 4 2007), Cumulative Index to Nursing & Allied Health Literature (1982 to May Week 4 2007), PubMed (May 30, 2007), EMBASE (1980 to 2007 May Week 21), Cochrane

Results

Our search strategy identified a total of 283 articles (Fig. 1). No unpublished articles were found. One [44] additional article was retrieved through reference review. Subsequently, 226 articles were excluded after title and abstract screening using the predefined inclusion and exclusion criteria. Of the remaining 57 articles, 26 were excluded: 1[18] was not published in English, 2[19], [20] did not report the outcome measurements in a quantitative manner, 7[21], [22], [23], [24], [25], [26],

Discussion

Among patients undergoing elective THR or TKA, antifibrinolytic agents reduce bleeding, reduce the risk of transfusion by almost 50% and do not appear to increase the risk of VTE. These observations are consistent with those found in the cardiovascular surgery literature [5], [6] and are of particular clinical importance given the observation that from 1995 to 2004 the rates of inpatient hip and knee replacements increased by 38% and 70% respectively in patients over age 65 in the United States

Conflict of interest statement

Dr Crowther holds a career investigator award from the Heart and Stroke Foundation of Ontario. Dr Crowther has received research funds, been on advisory boards, spoken on behalf and/or provided consultation services to: Pfizer, Sanofi Aventis, Leo Laboratories, Bayer, Boehringher Ingelheim, Artisan Pharma and Octapharma.

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