Abstract

Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in ca

Publication: J Cardiothorac Vasc Anesth 2005;19:4-10.

Tuesday, March 15th, 2005

Author: McDonald SB, Renna M, Spitznagel EL, Avidan M, Hogue CW, Moon MR, Barzilai B, Saleem R, McDonald JM, McDonald SB, Renna M, Spitznagel EL, Avidan M, Hogue CW, Moon MR, Barzilai B, Saleem R, McDonald JM,

Article
McDonald SB, Renna M, Spitznagel EL, Avidan M, Hogue CW, Moon MR, Barzilai B, Saleem R, McDonald JM, Despotis GJ. Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients. J Cardiothorac Vasc Anesth 2005;19:4-10.

Design
Single-center, retrospective observational study. Number of patients: 110. Study period: January 1998 – June 1999. Setting: Barnes-Jewish Hospital, St. Louis, Missouri.

Overview

Background
New antithrombotic agents, i.e. adenosine diphosphate (ADP)-mediated platelet inhibitors, glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitors, and low-molecular-weight heparins (LMWHs), are increasingly used by cardiologists in the treatment of acute coronary syndromes. Compared with conventional treatment with unfractionated heparin, these drugs may improve outcomes in certain patient groups. However, these patients are also at high risk for requiring urgent or emergent cardiac surgery, which raises the question whether newer antithrombotic drugs increase the risk of perioperative bleeding and its consequences, including allogeneic blood exposure and mediastinal reexploration. In this retrospective data review, the authors sought to evaluate whether the use of new antithrombotic drugs is associated with an increased risk for perioperative bleeding and blood transfusion in patients requiring coronary artery bypass grafting surgery (CABG).

Methods
All adult patients (n = 110) who underwent CABG (without combined valve operation) at Barnes-Jewish Hospital, St. Louis, Missouri, between January 1998 and June 1999 were included in the retrospective study. Patients were grouped according to preoperative antithrombotic regimen: group 1 (control, n = 55) received no antithrombotic drug; group 2 (n = 9), clopidogrel (Plavix®); group 3 (n = 17), enoxaparin (Lovenox®); group 4 (n = 14), any GP IIb/IIIa inhibitor, either abciximab (Reopro®), eptifibatide (Integrilin®), or tirofiban (Aggrastat®); and group 5, any combination of two agents (n = 15).

The following data related to perioperative bleeding were examined: cumulative mediastinal chest tube drainage at 12, 24, and after 24 hours postoperatively, the number of blood product transfusions, the total number of donor exposures, and the need for mediastinal reexploration for bleeding or tamponade.

Results
There were some differences in patient characteristics between groups. Patients receiving clopidogrel were older than control patients (p = 0.009). The GP IIb/IIIa group had shorter duration of aortic cross-clamping (p = 0.03) and more previous sternotomies (p = 0.03) than the control group. A great proportion of patients in the GP IIb/IIIa group received preoperative unfractionated heparin than in the control, clopidogrel, and enoxaparin groups (p ≤ 0.05); a greater number of patients in the group administered a combination of two agents were receiving preoperative unfractionated heparin when compared with control and enoxaparin groups (p < 0.002). More patients in the two-drug group were given aspirin preoperatively when compared with control group only (p = 0.02). Preoperative and initial postoperative laboratory values did not differ significantly. The proportion of patients requiring urgent or emergent surgery was higher among patients receiving platelet inhibitors, but multivariate analysis showed that urgent or emergent surgeries had no effect on the studied outcomes.

In all four groups receiving new antithrombotic drugs, patients were administered a significantly higher number of red blood cell (RBC) transfusions (p = 0.002), platelet transfusions (p = 0.006), and fresh frozen plasma transfusions (p = 0.048) than control patients. Total donor exposure was also significantly higher in the four groups than in the control group (p = 0.0003). The mean number of RBC units transfused was 2.0 ± 2.2 in the control group, 6.3 ± 6.1 in group 2, 6.5 ± 9.3 in group 3, 4.2 ± 2.8 in group 5, and 4.7 ± 2.7 in group 6, and the mean number of platelet concentrates transfused was 0.3 ± 0.7 in the control group, 1.8 ± 2.1 in group 2, 0.9 ± 1.6 in group 3, 0.9 ± 1.3 in group 5, and 1.2 ± 1.4 in group 6.

No difference in chest tube drainage at 12 and 24 hours was observed between groups, and chest tube drainage after the first 24 hours was not significantly increased in groups 1, 2, and 4. Only group 3 (enoxaparin) had a significantly greater total chest tube drainage than the control group (2,239 ± 3,252 mL vs. 1,115 ± 979 mL; p = 0.03). A greater percentage of patients in group 3 required mediastinal reexploration for bleeding versus control (3/17 vs. 0/55; p = 0.001). No surgical source for bleeding was identified in the patients who were reexplored.

Conclusion
The authors conclude that in this retrospective study newer antithrombotic agents were associated with greater transfusion rates and total donor exposures. Enoxaparin use was associated with greater overall blood loss and with higher incidence of mediastinal reexploration. The authors suggest that LMWH be discontinued and replaced by unfractionated heparin when surgery is anticipated. As newer antithrombotic agents are increasingly used, cardiologists, cardiac surgeons, and anesthesiologists should be aware of the potential bleeding risks for surgical candidates and the pitfalls of treating such complications.


Key Points
• New antithrombotic agents, i.e. adenosine diphosphate (ADP)-mediated platelet inhibitors, glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitors, and low-molecular-weight heparins (LMWHs), are increasingly used by cardiologists in the treatment of acute coronary syndromes.
• In this retrospective observational study of 110 adult patients coronary artery bypass grafting surgery, the authors found that administration of newer antithrombotic drugs was associated with a significant increase in the number of red blood cell, platelet, and fresh frozen plasma transfusions, as well as in total donor exposure.
• In the group receiving enoxaparin, total chest tube drainage was significantly greater than in the control group and a greater proportion of patients required mediastinal reexploration for bleeding.
• Currently, there is no available antidote to use in bleeding complications associated with LMWH.
• The authors suggest that clinicians (1) replace LMWH with unfractionated heparin and, if possible, postpone surgery for 24 to 48 hours; (2) use agents that have been shown to reduce bleeding with cardiac surgery (aprotinin, epsilon aminocaproic acid); (3) administer routine hemostatic therapy (platelets, plasma, desmopressin) for excessive bleeding, and when bleeding is excessive and unresponsive to routine therapy, consider administration of factor concentrates (e.g., recombinant factor VIIa).

Limitations
• Retrospective observational study with differences in patient demographics between groups, including other drug therapies such as aspirin which may have confounded the analysis
• Indications for blood product transfusion were not monitored and may have been empirically based.
• The increased chest tube drainage observed after 24 hours in the enoxaparin group was mainly due to excessive bleeding in only three patients.

SABM Rating:****

In Brief
A surgical procedure often disturbs the patient’s coagulation system, leading to an increased risk of either thrombosis or bleeding. In addition, a growing number of patients who undergo surgery are on antithrombotic therapy. Physicians should know the mechanisms of action, indications, means of substitution, and potential complications of both commonly used and newer antithrombotic agents as well the means to avoid excessive bleeding in relationship with the use of these drugs. In this retrospective observational study of 110 adult patients coronary artery bypass grafting surgery, the authors found that administration of newer antithrombotic drugs – clopidogrel (Plavix®), enoxaparin (Lovenox®), abciximab (Reopro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®), or any combination of two agents – was associated with a significant increase in the number of red blood cell, platelet, and fresh frozen plasma transfusions, as well as in total donor exposure. In the group receiving enoxaparin, total chest tube drainage was significantly greater than in the control group and a greater proportion of patients required mediastinal reexploration for bleeding. The authors suggest that clinicians (1) replace LMWH with unfractionated heparin and, if possible, postpone surgery for 24 to 48 hours; (2) use agents that have been shown to reduce bleeding with cardiac surgery (aprotinin, epsilon aminocaproic acid); (3) administer routine hemostatic therapy (platelets, plasma, desmopressin) for excessive bleeding, and when bleeding is excessive and unresponsive to routine therapy, consider administration of factor concentrates (e.g., recombinant factor VIIa). Further research is needed to evaluate the relative risk-benefit ratios of newer antithrombotic agents.