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Anesth Analg 2004;98:4-10 © 2004 International Anesthesia Research Society
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Abstract |
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In this study we sought to determine whether preoperative treatment with antiplatelet and/or anticoagulant drugs influences postoperative blood loss after coronary artery bypass graft surgery. Although prophylactic treatment to prevent ischemic events preoperatively is often necessary, the treatment frequently continues until there may be a risk of increased bleeding (i.e., within 5–7 days before surgery). With patient consent, a preincision blood sample was collected prospectively from 93 adult subjects who presented randomly. They consisted of 3 groups regarding their primary preoperative regimen: 1) no preoperative treatment within the week before surgery; 2) platelet adenosine diphosphate (ADP) receptor antagonist; 3) ADP receptor antagonist plus IV heparin. Postoperative chest tube drainage (24 h) in the group that received ADP antagonist alone was more (P < 0.05) than either of the other groups: 503 ± 56; 633 ± 55; 439 ± 29 mL (mean ± SEM) for Groups 1, 2, and 3, respectively. Combined treatment with ADP antagonist plus heparin infusion appeared to prevent the increased blood loss with the ADP antagonist alone. Preincision and postoperative plasma fibrinogen concentrations were largest (P < 0.05) in the group that received the combination treatment; mean ± SEM for groups 1, 2, and 3 preincision, 311 ± 17, 366 ± 16, and 423 ± 18 mg/dL, and postoperatively, 229 ± 16, 267 ± 13, and 312 ± 16 mg/dL. Postoperative fibrinogen showed strong dependence on preoperative fibrinogen in all groups (r = 0.576 to 0.825; P = 0.01 to 10-6). Prevention of the increased blood loss in the ADP receptor antagonist group by the addition of a heparin infusion may have been attributable to a conservation of coagulation factors, as evidenced by the increased plasma fibrinogen concentrations with combined prophylactic treatment.
IMPLICATIONS: The objective of this study was to determine whether preoperative treatment with antiplatelet and/or anticoagulant drugs influences the extent of blood loss in the 24-h period after cardiac surgery.
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Introduction |
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Several options are currently available for the hemostatic stabilization of patients scheduled for coronary artery bypass graft surgery (CABG). The use of antiplatelet or anticoagulant drugs to prevent the occurrence of ischemic events in the immediate preoperative period may have implications for perioperative and postoperative blood loss (1–5). Many cardiac surgery patients have received a drug that affects platelet GP IIb/IIIa receptor function at the time of their diagnostic cardiac catheterization, frequently within the 1-wk period before surgery. An irreversible antagonist of the platelet adenosine diphosphate (ADP) receptor, clopidogrel or ticlopidine, is the preferred approach at our institution. Blockade of the platelet ADP receptor leads to inhibition of the binding of fibrinogen to the platelet GP IIb/IIIa receptor complex, thereby preventing platelet aggregation from ADP stimulation (6). Platelet activation by collagen is partially inhibited by blockade of ADP receptors (7), whereas inhibition of platelet activation by thrombin appears to be only weakly impaired. However, there are somewhat conflicting data on the latter point (7,8). Also, inhibition of platelet activation by any mechanism may greatly decrease the net contribution of thrombin to platelet activation, as activated platelets play an important role in thrombin generation (6).
The primary objective of this investigation was to determine whether prophylactic treatment with antiplatelet and/or anticoagulant drugs influences the extent of chest-tube drainage in the 24-h period after CABG surgery. The choices for preoperative treatment of unstable angina are continually evolving, and are usually not made by the anesthesiology staff. Therefore, we evaluated the effects of different preoperative treatment modalities on several hemostatic indices.
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Methods |
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Blood was collected prospectively, with IRB approval, from 98 adult patients who presented randomly for CABG surgery. Written informed consent was obtained from all subjects. Some of the patients had combined valve replacement and coronary revascularization procedures, but no attempt was made to evaluate these patients separately. Five patients who required significant blood product supplementation during surgery or in the postoperative period were excluded from the data analyses, as the use of these products would confound the relationship between the preoperative prophylactic regimen and postoperative blood loss. Of the 93 patients who were studied, the different prophylactic preoperative regimens were represented as three groups. The first group (22 patients) represented patients who had received no antiplatelet or anticoagulant treatment within the week preceding surgery. This group was designated as NoRx. The second group (40 patients) received therapy in the week before surgery with an irreversible antagonist of the platelet ADP receptor (clopidogrel or ticlopidine). The ADP receptor antagonist was used primarily as a protective adjunct at the time of diagnostic cardiac catheterization in the week before surgery. The median number of days between the last or single dose of ADP antagonist and the day of surgery in this group was 3 days. The usual dose of clopidogrel was 300 mg, and the usual dose of ticlopidine was 500 mg. A single 325-mg dose of aspirin was also given at cardiac catheterization. The third group (31 patients) received the platelet ADP antagonist and aspirin at cardiac catheterization and a low level IV heparin infusion in the range of 1000–2000 U/h during hospitalization in the days preceding surgery; the heparin infusion continued until the time of surgery. The median number of days between the last dose of ADP antagonist and the day of surgery in this group was also 3 days. Some of the patients in Groups 2 and 3 also received therapy with low molecular weight heparin (enoxaparin) in the week before surgery. However, when enoxaparin was used, it was discontinued at least 12 h before surgery.
Antifibrinolytic therapy for most patients was a single 10-g dose of 
-aminocaproic acid before the start of surgery. Alternatively, a small percentage of patients received aprotinin (Table 1). All surgeries were performed in conjunction with cardiopulmonary bypass (CPB); after heparinization, heparin dosage was adjusted throughout to maintain a kaolin-activated clotting time (ACT) more than 480 s. Two units of whole blood were sequestered after heparinization, but before the start of CPB. This blood was reinfused after weaning from CPB. After CPB, heparin was neutralized with protamine to normalize the ACT. Blood from the cell saver was returned before the patient left the operating room. Blood drained via the chest tubes during the postoperative period was not returned to the patient.
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A blood sample was taken in the operating room before incision, and on arrival in the postoperative care unit. Blood was drawn into Vacutainer blue stopper tubes (Becton Dickinson, Franklin Lakes, NJ) containing 3.8% sodium citrate (9:1 vol/vol). The following analyses were done on both samples: platelet count, hematocrit percent, hemoglobin concentration, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen concentration. A portion of the preincision blood plasma was frozen for subsequent determination of D-dimer concentration by an enzyme immunoassay (EIA) (Quest Diagnostics, Teterboro, NJ) in anticipation of its possible value for detection of differences in preoperative microembolic activity among the groups. Although not planned in advance, prothrombin fragment 1.2 levels were determined on the preincision blood sample (to the extent that there was sufficient plasma remaining for these analyses) by EIA (Hemostasis Reference Laboratory, Hamilton, ON or Quest Diagnostics) as another potential indicator of initiation of microembolic activity. Postoperative chest-tube drainage was recorded at 1, 6, 12, and 24 h.
Statistical comparisons among the three groups were conducted using analysis of variance followed by post hoc multiple group comparisons with the Newman-Keuls test. Covariance analysis was used for the data that represented repeated measures on the same patients (postoperative chest-tube drainage; 1–24 h). 
2 analysis was applied to the ratios of males to females, incidences of previous cardiac operations, and the frequencies of aprotinin use among the groups. Pearson correlation analysis was used for the relationships between preoperative and postoperative plasma fibrinogen concentrations.
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Results |
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No differences were found among the three groups in regard to demographic factors, incidence of prior cardiac surgery, platelet counts, hematocrit percentages, hemoglobin concentrations, and PT for the preoperative period (Table 1). Comparisons were not made on preoperative aPTT because one of the groups was receiving, or had just been terminated from, IV heparin infusions at the time preoperative blood was sampled, and the results could have been confounded by the continued presence of heparin.
Most of the factors that were tabulated and tracked intraoperatively, including the choice of antifibrinolytic drug, number of vascular grafts, extracorporeal circulation temperature, blood product transfusions, desmopressin use, and estimated blood loss were not different among the groups (Table 1). However, the ADP antagonist plus IV heparin group showed the shortest aortic cross-clamp times and extracorporeal circulation times; these times were statistically different from the NoRx group (P < 0.05).
For the postoperative period, body temperature on arrival in the intensive care unit, platelet counts, hematocrit percentage, hemoglobin concentration, PT, aPTT, and blood product transfusions showed no significant differences among the groups (Table 1).
Cumulative postoperative chest tube drainage was significantly affected by the preoperative prophylactic regimen. Data over the 24-h postoperatively showed that the group that had received the platelet ADP receptor antagonist (without heparin infusion) showed statistically more blood loss in comparison with the other groups (Fig. 1). Of particular interest was the fact that the addition of a preoperative heparin infusion to patients who had received the platelet inhibitor appeared to prevent the excess blood loss of the ADP antagonist alone.
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P = 0.05 vs. NoRx, and ADP antagonist + IV heparin.Plasma fibrinogen levels were also affected by the preoperative treatments. The group that received both a platelet inhibitor and a heparin infusion preoperatively had the highest average preoperative fibrinogen level (P < 0.05 versus ADP antagonist alone and versus NoRx) (Fig. 2A). Preoperative fibrinogen level in the ADP antagonist alone group was also more (P < 0.05) than in the NoRx group (Fig. 2A). Postoperative fibrinogen levels were also highest in the group that received both the platelet inhibitor and heparin infusion (P < 0.05) (Fig. 2B). There were significant positive correlations between preoperative and postoperative fibrinogen levels in all three groups (Fig. 3A, B, C).
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Preincision plasma D-dimer concentrations were determined from a random sample of 11 patients from each group. More than 90% of the samples were less than the upper limit of the normal reference range of 120 ng/mL, and there were no differences among the groups. The mean ± SEM for the groups were NoRx, 30 ± 4 ng/mL; ADP antagonist, 41 ± 10 ng/mL; ADP antagonist plus IV heparin, 65 ± 24 ng/mL.
In an effort to determine how the combination of a platelet ADP inhibitor and heparin infusion avoided the excess blood loss with the ADP antagonist alone (Fig. 1), and resulted in higher plasma fibrinogen levels (Fig. 2A, B), remaining blood samples from the groups were analyzed for prothrombin fragment 1.2. Although there were too few samples to permit a statistical comparison, it was noteworthy that virtually all of the samples showed marked evidence of initiation of coagulation in the preoperative period, despite antiplatelet/anticoagulant therapy. Levels of prothrombin fragment 1.2 were well above the upper limit of the normal reference range (1.24 nmol/L). Average levels of prothrombin fragment 1.2 (and ranges), in nmol/L, for the groups were as follows: NoRx, 5.89 (1.31–19.6); ADP antagonist, 5.89 (1.20–54.0); ADP antagonist + IV heparin, 3.41 (1.32–8.8).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This investigation concerns the effect of preoperative prophylaxis with antiplatelet/anticoagulant drugs on blood loss after cardiac surgery. General recommendations include the avoidance of the use of aspirin within 5 days before surgery, use of the platelet ADP receptor antagonists, clopidogrel and ticlopidine, within 7 days and 10–14 days before surgery, respectively, and use of low molecular weight heparin (enoxaparin) within 12 h before surgery (9). In this study, enoxaparin was discontinued approximately 12 h or more before surgery in all patients who received it. Patients in the NoRx group received no therapy within the recommended waiting periods before surgery. However, because of various clinical considerations, patients in the other two groups received antiplatelet/anticoagulant therapy within the 1-week period preceding surgery.
Patients who received a platelet ADP receptor antagonist alone during the preoperative period showed increased chest tube drainage throughout the 24-h postoperative period (Fig. 1). This finding might be expected, and has been reported previously (1,3,5,10,11). However, it has also been shown in experimental animals that prevention of platelet aggregation with the use of a reversible GPIIb/IIIa receptor inhibitor resulted in a conservation of platelets and reduced postoperative bleeding (12). It was unexpected that the addition of a preoperative low-level heparin infusion to the ADP antagonist regimen would completely prevent the increased blood loss effect of the ADP antagonist given alone. The mechanism by which the preoperative combination therapy protected against the excess blood loss seen with the ADP antagonist alone is not known. We speculate that the combined treatment may have more effectively prevented microemboli formation in the preoperative period, thereby conserving coagulation factors and providing improved hemostatic competency through the postoperative period. The only coagulation factor that was measured was plasma fibrinogen, which may be a marker of general conservation of coagulation factors. Plasma fibrinogen concentration for the group that received ADP antagonist plus IV heparin was largest in preoperative and postoperative plasma (Fig. 2A, B).
The improved outcome regarding postoperative blood loss in this study with a combination of platelet inhibition and heparin infusion is of interest in relation to the findings in the PRISM-PLUS study (Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms) (13). In that study, tirofiban plus heparin infusion was compared in a double-blinded design in patients with unstable angina and non-Q-wave myocardial infarction. Study drugs were administered for a mean (± SD) of 71.3 ± 20 h after randomization. The combination of tirofiban and heparin therapy was superior to tirofiban or heparin alone at 48 h, 7 days, 30 days, and 6 mo for reduction of many adverse end-points (refractory ischemia, myocardial infarction, readmission for unstable angina, death, and composite end-point). These findings are consistent with an additive or synergistic reduction in microembolic activity being a reasonable result from a combination of platelet inhibition and inhibition of thrombin generation by heparin. Activated platelets greatly accelerate the reaction rate of factor Xa/factor Va generation of thrombin, and thrombin, in turn, activates platelets in this positive feedback loop (Fig. 4) (14–16). The combined effects of an ADP antagonist and heparin block this feedback cascade at two different sites. This possible synergism may also have continued intraoperatively.
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If the increased plasma fibrinogen concentration that we observed with the ADP antagonist plus IV heparin therapy was a reflection of decreased microembolic activity, as suggested above, it is of interest that preoperative fibrinogen had such a strong contribution to postoperative fibrinogen levels for all groups (Fig. 3A, B, C), Thus, maintenance of hemostatic competency in the preoperative period, without sacrificing protection against ischemic events, is a desirable objective.
A somewhat surprising finding was that the average aortic cross-clamp time as well as extracorporeal circulation time was the shortest in the group that received combination prophylactic therapy (Table 1). Because this was the group with the smallest postoperative chest tube drainage, we examined whether there was a relationship between these two measurements over the combined data for the three groups. The Pearson correlation coefficient between aortic cross-clamp time and 24-h postoperative blood loss was r = 0.104; the correlation between extracorporeal circulation time and 24-h blood loss was r = 0.042. Thus, there was no relationship between these variables. We do not have an explanation for the significantly shorter cross-clamp and pump times in the group that received the ADP antagonist and heparin infusion preoperatively.
In an attempt to detect possible differences in preoperative microembolic activity among the three groups, we analyzed plasma D-dimer and prothrombin fragment 1.2. In a preliminary study, we had examined D-dimer levels in patients similar to those in the present study using a hospital based semiquantitative screening assay. Because that study showed no evidence of increased D-dimer preoperatively, we only relegated plasma samples from 11 patients randomly from each group for quantitative determination of D-dimer. There were no apparent differences among the groups, and only a few patients had D-dimer levels more than the upper limit of the normal range. In comparison, prothrombin fragment 1.2 levels exceeded the upper limit of the normal range (1.24 nmol/L) in 54 of 56 patients who were studied. Some of the highest levels were observed in the NoRx group and the ADP antagonist alone group. Prothrombin fragment 1.2 levels more than 10 nmol/L for the three groups were as follows: NoRx, 2 of 11 patients; ADP receptor antagonist alone, 5 of 29; ADP antagonist + IV heparin, 0 of 16.
Prothrombin fragment 1.2 is the first peptide that is cleaved from prothrombin in the activation to thrombin (Fig. 4), and it is considered to be a sensitive marker of initiation of coagulation (17). The high levels of this coagulation marker that were observed are consistent with the active coronary inflammatory process that has been documented in unstable angina (18). The range of prothrombin fragment 1.2 values in our patient groups was wider than that observed preoperatively in some studies (19,20), and is probably related to the patient population. However, the lowest values in each of our groups overlapped those that have been observed by others. Investigation of prothrombin fragment 1.2 was not originally planned for this study, and the number of patients in each group was too small to draw statistical inferences. However, this would appear to be an important approach for future studies. Patients with left ventricular assist devices, who have normal values for routine screening variables such as PT, aPTT, and platelet count, have shown marked activation of clotting activity, i.e., increased thrombin-antithrombin complex and prothrombin fragment 1.2 (21). Also, in an experimental study with baboons undergoing CPB, the combination of platelet inhibition (tirofiban) and heparin therapy significantly reduced prothrombin fragment 1.2 levels when compared with heparin therapy alone (22).
Our observation that platelet ADP receptor antagonism in combination with heparin infusion preoperatively prevented the excess blood loss seen postoperatively with an ADP antagonist alone may have clinical value; the timing in the use of such antagonists in relation to their risks for excessive bleeding is frequently unavoidable. Although no mechanism can be provided for this effect, our data suggest that the combination therapy may have conserved coagulation factors in the preoperative period, and that this benefit was extended into the postoperative period.
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Acknowledgments |
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The authors thank Aravind Pothula, BA, Andrew S. Inchiosa, and Mario E. Inchiosa, PhD, for their contributions to the compilation, statistical analysis, and formatting of the data.
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Footnotes |
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Presented in part at the 23rd Annual Meeting of the Society of Cardiovascular Anesthesiologists, Vancouver, BC, Canada, May 5–9, 2001.
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References |
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