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Ann Thorac Surg 1996;61:774-775
© 1996 The Society of Thoracic Surgeons

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Correspondence

Tranexamic Acid Use During Coronary Artery Bypass Grafting

Divisions of Cardiac Surgery, and Hematology, University of Ottawa Heart Institute, Ottawa Civic Hospital, 1053 Carling Ave, Ottawa, Ont, K1y 4E9, Canada

To the Editor:

Due to the current concerns of infectious complications related to homologous blood transfusion, extensive research is being directed to develop means to decrease blood loss during cardiac operations. The most successful pharmacologic strategies involve the prophylactic administration of drugs that inhibit fibrinolysis, such as the nonspecific protease inhibitor aprotinin, or the synthetic lysine analogues, such as 6-amino-hexanoicacid (-aminocaproic acid) and trans-p-aminomethyl-cyclohexanecarboxylic acid (tranexamic acid). Several studies have already supported that these medications effectively decrease postoperative bleeding after open heart operations [1]; however, their use has not yet been universally accepted due to their cost, as well as to the concern that they may induce a state of hypercoagulability after operation [2].

The clinical efficacy of tranexamic acid administered during coronary artery bypass grafting was addressed by Rousou and associates [3] in a cohort study involving patients undergoing elective nonreoperative procedures. Rousou and associates were able to demonstrate a significant decrease in both the total amount of postoperative bleeding and in the requirements for homologous blood products in patients receiving tranexamic acid as compared with controls; however, they did not demonstrate a significant increase in the incidence of thromboembolic events in the treated group.

We would like to address two issues in this article. The first relates to the mechanism of action of the aminocarboxylic acids. Rousou and associates state that the pharmacologic action of tranexamic acid involves its role as ``a competitive inhibitor of plasminogen activation and at higher concentrations a noncompetitive inhibitor of plasmin.'' It is perhaps more appropriate to describe the mechanism of action in more detail given that in vitro, tranexamic acid accelerates the conversion of plasminogen to plasmin [4]. The aminocarboxylic acids (such as tranexamic acid or -aminocaproic acid) bind to the lysine binding site of plasminogen, thereby inducing a conformational change in the molecule, making it more susceptible to proteolytic action by plasminogen activators. However, this same binding blocks the functional activity by occupying the lysine binding site, thus preventing binding to fibrin and hence fibrinolysis. There is also recent evidence that tranexamic acid may act to inhibit plasmin-induced platelet activation during cardiopulmonary bypass. Soslau and associates [5] demonstrated a preservation of platelet dense granule adenosine diphosphate content after cardiac operations. In a subsequent in vitro study, they confirmed that preincubation of plasmin with tranexamic acid inhibited plasmin-induced platelet activation. In conclusion, these studies suggest that the key mechanisms of action of tranexamic acid are related to partial platelet preservation and inhibition of plasmin binding to the lysine-binding site of the fibrin molecule.

The second issue relates to the choice of tests for the analysis of clinical variables that are proportions, ie, mortality, perioperative rates of myocardial infarction, deep venous thrombosis and pulmonary embolism, and the proportion of patients receiving blood products. Rousou and associates used a ``two-sample t test for each variable,'' and it is our impression that Fisher's exact test or the ² test is indicated in such an analysis. This discrepancy is of particular concern, as superficial analysis of the data from the tranexamic acid group suggests that several clinical problems may be increased in the treatment group (ie, use of intraaortic balloon pump, perioperative creatine kinase- MB level, deep venous thrombosis, pulmonary embolism, mortality, and most significantly myocardial infarction as cause of death). What would a repeat analysis using the ² statistic demonstrate?

References

1. Fremes SE, Wong BI, Lee E, et al. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994;58:1580–8.[Abstract]
2. Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031–8.[Abstract]
3. Rousou JA, Engelman RM, Flack JE III, Deaton DW, Owen SG. Tranexamic acid significantly reduces blood loss associated with coronary revascularization. Ann Thorac Surg 1995;59:671–5.
4. Takada A, Sugawara Y, Takada Y. Enhancement of the activation of Glu-plasminogen by urokinase in the simultaneous presence of tranexamic acid or fibrin. Haemostasis 1989;19:26–31.[Medline]
5. Soslau G, Horrow J, Brodsky I. Effect of tranexamic acid on platelet ADP during extracorporeal circulation. Am J Hematol 1991;38:113–9.[Medline]

Reply

Division of Cardiac Surgery, Baystate Medical Center, Springfield, MA 01199

To the Editor:

We appreciate the comments by Drs. Rubens and Wells regarding our article. Their comments on the mechanism of action of tranexamic acid, which point to the possible dual action of tranexamic acid in preventing postoperative bleeding, are absolutely correct, with the platelet preservation component of its beneficial effects being more recently recognized.

In regard to the choice of test for analysis of clinical variables, we would like to clarify that although not clearly stated in the article, tests for binary data were done using the ² and Fisher's exact tests. The results of the data analyses in our article are, therefore, correct. Our description of the statistical analysis in our article should have read ``Comparisons of results between the two groups were done by the two sample t test for continuous variables and by either the ² or Fisher's exact test for dichotomous variables.''

We thank Rubens and Wells for their comments on our article, and we appreciate their clarifications. We would like to emphasize again that the analysis and conclusions remain the same using all possible statistical methods applicable to these data.

This article has been cited by other articles:

				C. Huet, L. R. Salmi, D. Fergusson, A. W. M. M. Koopman-van Gemert, F. Rubens, and A. Laupacis A Meta-Analysis of the Effectiveness of Cell Salvage to Minimize Perioperative Allogeneic Blood Transfusion in Cardiac and Orthopedic Surgery Anesth. Analg., October 1, 1999; 89(4): 861 - 861. [Abstract] [Full Text] [PDF]

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Fraser Rubens John A. Rousou Richard M. Engelman Joseph E. Flack, III David W. Deaton Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rubens, F. Articles by Owen, S. G. Search for Related Content PubMed PubMed Citation Articles by Rubens, F. Articles by Owen, S. G.