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J Thorac Cardiovasc Surg 1994;107:1376-1377
© 1994 Mosby, Inc.

LETTERS TO THE EDITOR

Tranexamic acid after bypass: Too late to help?

Oslo Heart Center
Pilestredet 32
0027 Oslo, Norway

Reply to the Editor:

We appreciated the comments of Dr. Horrow and colleagues concerning our article on the effect of tranexamic acid (Cyclocapron) in elective coronary artery bypass operations. In 100 consecutive patients we demonstrated a modest reduction in postoperative bleeding in patients who were given tranexamic acid after protamine compared with a subsequent group of 100 consecutive patients serving as a control group. A conventional, nonpharmacologic blood conservation protocol equalized the total hemoglobin loss. We expressed our concern about the rate of postoperative myocardial infarction of 5% in the tranexamic group compared with 1% in the control group. All operations were performed by the same surgeon and anesthesiologist.

Horrow and colleagues claim that our observational study suffers from "extreme bias" without pinpointing exactly the kind of bias—selection bias, information bias, or confounding bias. ^1-3 We would like to point out that our study had a prospective cohort design, and there were no differential sample distortions when exposure (tranexamic acid, yes/no), postoperative bleeding, or perioperative myocardial infarction (MI) were considered. As for the information bias, there were no patient data lost, and the possibility of nondifferential misclassification of the exposure to the drug and postoperative bleeding, which could dilute the effect, was improbable in our situation. For the confounder bias, we used multivariate models to control for potential confounders for the two end points. Finally, it must be obvious that the number of surgeons included in clinical studies should be kept at a minimum when such a sensitive and individual-related parameter as postoperative bleeding is being evaluated. This must be equally true in randomized studies, when smaller groups of patients are being compared, as reported by Horrow and colleagues ⁴ (18 versus 20 patients in each group).

Also, apart from the figures, the results from our control group of 100 patients, with no homologous blood transfusions and a hemoglobin concentration of 121 gm/L at discharge, clearly support our conclusion that neither tranexamic acid nor other drugs are necessary components in a blood conservation protocol during elective coronary artery bypass operations.

Our major concern when introducing a potent antifibrinolytic drug like tranexamic acid, which had no beneficial effect on hemoglobin loss, was the frequency of perioperative MI. Although the difference was not statistically significant, the 5% prevalence (five patients) of perioperative MI in the tranexamic group, compared with 1% in the control group, did disturb us. Assessing an effect of tranexamic acid on perioperative MI needs a larger study. In fact, if we consider a prevalence of perioperative MI of 3% after coronary artery bypass and if we are willing to pinpoint a relative risk of 2 (RR = 2) for tranexamic acid versus placebo, a type I error of 5%, and a power of 80%, a total number of 814 patients in each group would be necessary for such a trial. In the references put forward by Horrow and colleagues, there is a power deficiency concerning the end points perioperative MI and cardiovascular events. In the studies referred to, the estimated statistical power ranged from 3% ⁵ via 10% ⁴ to 35%. ⁶

With regard to the statistical methods we have been using, we refute the claims of Horrow and colleagues and suggest that they reread the Methods section in our article.

We agree that there are theoretical advantages of administrating antifibrinolytic drugs before the start of bypass, ⁷ but to the best of our knowledge no clinical investigation on timing of tranexamic acid administration has yet been undertaken.

We appreciate this opportunity to point out once again that tranexamic acid should not be administered routinely in elective coronary artery bypass operations, because the effect on bleeding can be equalized by a nonpharmacologic blood conservation protocol. ⁸ The potential hazards of the drug should not be overlooked.

References

1. Kleinbaum D, Kupper L, Morgenstern H. Epidemiologic research. New York: Van Nostrand Reinhold Company, 1982.
   
2. Rothman K. Modern epidemiology. Library of Congress. Boston: Little Brown, 1986.
   
3. Rumeau-Rouquette C, Bréard G, Padieu R. Méthodes en épidémiologie. Paris: Médecine-Sciences Flammarion, 1989.
   
4. Horrow JC, Hlavacek J, Strong MD, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J THORAC CARDIOVASC SURG 1990;99:70-4.[Abstract]
   
5. Vander Salm TJ, Ansell JE, Okike ON, et al. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double-blind randomized study. J THORAC CARDIOVASC SURG 1988;95:538-40.[Abstract]
   
6. DelRossi AJ, Cernaianu AC, Botros S, Lemole GM, Moore R. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989;96:27-30.[Abstract/Free Full Text]
   
7. Soslau G, Horrow J, Brodsky I. Effect of tranexamic acid on platelet ADP during extracorporeal circulation. Am J Hematol 1991;38:113-9.[Medline]
   
8. Ovrum E, Åm Holen E, Abdelnoor M, Oystese R. Conventional blood conservation techniques in 500 consecutive coronary artery bypass operations. Ann Thorac Surg 1991;52:500-5.[Abstract]
   

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