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Department of Anaesthesiology and Critical Care Medicine, University Hospital Innsbruck, Innsbruck, Austria
To the Editor:
We read with interest the article by Pothula et al. (1) investigating effects had by preoperative ADP antagonists with or without heparin on postoperative blood loss after cardiac surgery. This is an important issue because anesthesiologists are increasingly confronted with patients on platelet-active drugs. The authors found that patients receiving ADP antagonists and additional low-dose heparin exhibited a significantly minor blood loss as compared with the control group and the group receiving only ADP antagonists. This result was explained by a possible beneficial effect of heparin in preventing formation of microemboli and thus preserving coagulation factors until the postoperative period. This assumption is interesting, since exogenous heparin or endogenous heparinoids are usually associated with increased bleeding and all patients were on full heparin dosage during CBP. Furthermore, with the exception of fibrinogen, no coagulation factor was measured pre- or postoperatively. In addition, the authors made no attempt to measure platelet function preoperatively, which seems necessary to guarantee that groups are comparable. Clopidogrel is six times more potent than ticlopidine and shows linear pharmacokinetics, while ticlopidine does not (2). However, clopidogrel-induced platelet inhibition exhibits considerable individual heterogeneity (3). Furthermore, it is not clear how many patients in each group received clopidogrel or ticlopidine or whether patients received one single or repeated doses, which influences half-life, especially for ticlopidine. Why did 13% of patients in the treatment groups receive aprotinin and 4.3% the combination of aprotinin and 
-aminocaproic acid, while this was true for 9% and 0% of control patients, respectively? Data from animal experiments show that aprotinin partially reverses effects of thienopyridines in a dose-dependent manner (4). Lastly, concentrations of fibrinogen already varied considerably between groups at baseline. Although differences in aortic cross-clamping time and extracorporeal circulation time were investigated as possible confounders, the obvious difference in preoperative fibrinogen concentrations did not correlate with the amount of blood loss. Since intraoperative blood loss was equal in all groups, it was to be expected that postoperative concentrations of fibrinogen would correlate well with preoperative values in all groups (5), provided that fluid therapy, which itself influences hemostasis, was also comparable between groups.
Consequently, the causal relationship between platelet antagonists with or without heparin therapy and the reported postoperative blood loss seems quite questionable. Moreover, since several confounders cannot be excluded, results should be interpreted with caution.
References
Department of Anesthesiology Department of Pharmacology, New York Medical College, Valhalla, NY
In Response:
Fries et al. note our apparent paradoxical finding that a combination of platelet inhibition and anticoagulation with heparin preoperatively lead to decreased blood loss postoperatively. As they also noted, our observations may be of importance in view of the increasing use of antiplatelet drugs. They question our grouping together patients who received either clopidogrel or ticlopidine. We did so on the basis that both drugs have similar mechanisms of action, i.e., they are both irreversible inhibitors of platelet ADP receptors. Potency is not an issue; it would be expected that they were used at doses that have equal efficacies. The great majority of the patients received clopidogrel. Typically, a single dose was given in conjunction with cardiac catheterization in both groups.
Regarding the frequency of administration of -aminocaproic acid and/or aprotinin, there were no statistical differences among the three groups; therefore, an influence from the choice of antifibrinolytic therapy, if any, would be expected to be uniformly distributed among the groups.
We differ from Fries et al. in regard to several parameters that we regard as outcome measures rather than baseline differences among the groups. Thus, we consider the higher plasma fibrinogen concentrations at the end of the preoperative treatment period, their apparent contribution to improved hemostasis postoperatively, and decreased surgical and extracorporeal circulation times as favorable outcomes of the combined treatment with ADP-receptor antagonist and heparin. We have not claimed to have established a casual relationship between the combination therapy and certain favorable outcomes; however, our findings suggest possible further areas of study.
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