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Ann Thorac Surg 1996;62:1667-1668
© 1996 The Society of Thoracic Surgeons
DR BENJAMIN P. BIDSTRUP (Townsville, Australia): I thank Dr Lemmer and associates for the opportunity to review the manuscript today. I have a number of questions and comments related to this. This study will certainly help allay some of the fears that people have had about the possible association of aprotinin with perioperative MI. You certainly have quite a powerful study, and in combination with other previous studies that have looked at this, I think we can try and lay these concerns to rest.
I do, however, have some other concerns. In the manuscript you have pointed out that the use of the synthetic antifibrinolytic agents was allowed in the pump-prime--only group. Six percent of those patients received 
-aminocaproic acid. Given that there is a significant difference in the mode of action of the synthetic antifibrinolytics and the mode of action of aprotinin, you might care to comment on this combination. I certainly would not recommend the combined use of both of these drugs because of the lack of safety data, in particular of the synthetic antifibrinolytics. It is possible that -aminocaproic acid is associated with an increase in the incidence of MI.
DR LEMMER: Thank you, Dr Bidstrup. The patients enrolled in the study were not given tranexamic acid or -aminocaproic acid prophylactically. There was an exclusion criterion, in that patients who needed such drugs on a prophylactic basis were not enrolled in the study.
However, the investigators were free to use these agents postoperatively if they saw fit, and of course, they did not know which patients had received aprotinin or placebo. As noted, there was an increased incidence of -aminocaproic acid use in the pump-prime--only group. Whether this is a statistically significant difference, I do not know. Whether this can be correlated with the increase in the incidence of possible MIs, I also do not know. But I would, however, echo your statement that using these drugs in combination would not be currently recommended. I am not aware of a large series of patients demonstrating the safety of combining aprotinin with either tranexamic acid or -aminocaproic acid.
DR THOMAS Z. LAJOS (Buffalo, NY): I congratulate Dr Lemmer and associates for a very well conducted experiment on aprotinin. I would like to discuss and address the question of dosage. In Buffalo in 1971 we investigated [1] the efficacy of -aminocaproic acid, aprotinin, and estrogen in controlling bleeding after open heart operations. At that time, the dose of aprotinin was a 4-hour intravenous infusion of 400,000 KIU, which is almost one third of your low dose, and we have shown a significant decrease in bleeding. Less bleeding has occurred also with estrogen and -aminocaproic acid.
I think the dose of aprotinin is still questionable, especially since, in a lower dose, its effect on the clotting system seems to be safer and also has less effect on the antithrombin cascade. The fact that you used lower doses in your study is a good trend, but further studies of even lower doses are preferable, as far as we are concerned. My question, therefore, is: Are you conducting a study with your sponsors that in the future would try to depict the right lower dose?
DR LEMMER: The major studies demonstrating safety and graft patency and other important aspects of aprotinin use have employed one or all of the three doses I described today. To go to lower doses would be embarking into new territory. Intuitively it makes sense that a smaller dose of a drug should have a lower incidence of side effects, but for a nonspecific enzyme inhibitor such as aprotinin, which has different actions at different concentrations, this may not be the case. Aprotinin's inhibition of serine protease enzymes affects both fibrinolytic and coagulation processes. It has been hypothesized that, at low serum concentrations, aprotinin may act as a very effective antifibrinolytic with little anticoagulant effect, but at higher concentrations, it acts to inhibit both coagulation and fibrinolysis, the latter combination resulting in a balance that decreases bleeding without thrombotic complications. Thus, comparing high doses to low doses becomes a little tricky if the drug works differently at different concentrations.
This hypothesis, however, remains unproved. It could, however, account for our finding that possible MIs occurred more frequently in the group of patients who received the lowest aprotinin dose tested.
DR W. R. ERIC JAMIESON (Vancouver, BC, Canada): I have just a short comment. We conducted a randomized trial on reoperation with high-dose aprotinin versus placebo. We also identified the reduction in blood loss and the reduction in blood transfusion. The mortality in our control group was 2%, and the mortality in our treated group was 12%; this was due to myocardial infarction in the distribution of endarterectomized vessels. I wonder if you could comment on that. Did you identify any problems with vessels that were endarterectomized that thrombosed, causing MI in the treated groups?
DR LEMMER: How many patients did you have in your groups, and what was your method of anticoagulation during bypass?
DR JAMIESON: Our method of anticoagulation was what was considered standard for the use of aprotinin with a high dose of heparin. This was a single-center, randomized study in which we had approximately 40 to 50 patients per group and all had reoperation.
DR LEMMER: The possibility of graft thrombosis in conjunction with aprotinin use has been raised many times, and I think it would be natural to extend that concern to both the endarterectomized and the smaller target vessels. Large, randomized, blinded studies such as the one I presented today have not identified a difference in definite MI between patients who received aprotinin and those who did not. But the effect of aprotinin on endarterectomized vessels has not been previously reported as far as I am aware, and we look forward to the publication of a report that addresses this question. Certainly, it is possible that coronary arteries already at increased risk for early closure, such as endarterectomized and smaller ones, may be more likely to be adversely affected by drugs that interfere with the process of fibrinolysis. We, however, did not identify mortality differences, such as the one you described, in our study that involved 20 hospitals, 700 patients, more than 2,000 grafts, and a large number of surgeons.
Reference
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