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Ann Thorac Surg 2003;76:124-128
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Effects of preoperative enoxaparin versus unfractionated heparin on bleeding indices in patients undergoing coronary artery bypass grafting

^a Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston-Salem, NC, USA
^c Office of Research, Wake Forest University School of Medicine, Winston-Salem, NC, USA
^b Department of Pharmacy, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina, USA

Accepted for publication January 24, 2003.

^* Address reprint requests to Dr Kincaid, Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
e-mail: tkincaid{at}wfubmc.edu

Presented at the Forty-ninth Annual Meeting of the Southern Thoracic Surgical Association, Miami Beach, FL, Nov 7–9, 2002.

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusions Discussion References

 
BACKGROUND: We examined the effects of preoperative administration of enoxaparin (ENOX), a low-molecular-weight heparin, on bleeding indices and transfusion rates in patients undergoing coronary artery bypass grafting (CABG).

METHODS: Patients undergoing isolated CABG between 1997 and 2002 who received preoperative ENOX or a continuous infusion of unfractionated heparin (UFH) were randomly divided into three groups: continuous UFH, ENOX last administered more than 12 hours before surgery (ENOX > 12), and ENOX administered less than 12 hours before surgery (ENOX < 12). Perioperative hemoglobin values, transfusion rates, and bleeding complications were compared.

RESULTS: A total of 69, 58, and 34 patients comprised the UFH, ENOX > 12, and ENOX < 12 groups, respectively. Preoperative demographics and hematologic data were similar among the groups. Compared with the UFH group, the ENOX < 12 group had significantly lower postoperative hemoglobin values (9.6 ± 1.3 g/dL versus 10.4 ± 1.2 g/dL, p < 0.05), higher transfusion rates (73.5% versus 50.7%, p < 0.05), and required more total packed red cells per patient (882 ± 809 mL versus 472 ± 626 mL, p < 0.05). A nonsignificant increase was noted in the risk of returning to the operating room for bleeding in patients who had received ENOX compared with patients receiving UFH (6.5% versus 2.9%).

CONCLUSIONS: The preoperative use of ENOX less than 12 hours before CABG is associated with lower postoperative hemoglobin values and higher rates of transfusion than continuous UFH.

	Introduction

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Anticoagulation has been the cornerstone of managing acute coronary syndrome (ACS) since the 1970s when unfractionated heparin (UFH) was shown to benefit patients with acute myocardial infarction [1–3]. Since that time, various formulations of low-molecular-weight heparin (LMWH) have been used increasingly in the management of ACS. Low-molecular-weight heparin is a potent inactivator of coagulation Factor Xa and has several advantages over UFH including more predictable dose–response characteristics, improved bioavailability, ease of administration, and a decreased need for laboratory monitoring. In the management of ACS, several studies have demonstrated an improved efficacy of enoxaparin (ENOX), a LMWH, over UFH [4–6]. A meta-analysis [7] that involved a total of 7,081 patients enrolled in two large randomized controlled trials [5, 6] comparing UFH with ENOX demonstrated a 20% reduction in the rate of death, myocardial infarction, or urgent revascularization with an increased risk of minor, but not major bleeding with the use of ENOX. Because of these data, the American College of Cardiology/American Heart Association recommend, as a Class IIa guideline (weight of evidence/opinion is in favor of usefulness/efficacy), that ENOX is preferable to UFH in patients with unstable angina or non–ST-segment elevation myocardial infarction, unless coronary artery bypass grafting (CABG) is planned within 24 hours [8].

Because of their anticoagulant potency, relatively long half-life, and lack of reversibility, LMWHs have the potential to cause significant bleeding in patients who require surgery while on these agents. In fact, a study in patients undergoing CABG while on the LMWH dalteparin revealed a 50% increase in perioperative blood loss and a higher incidence of blood transfusion compared with patients on UFH [9]. Some data suggest similar complications after CABG in patients receiving ENOX. For example, Jones and colleagues [10] recently demonstrated an increased incidence of reexploration for bleeding in patients receiving preoperative ENOX within 48 hours of surgery compared with patients receiving preoperative UFH. Enoxaparin has been suggested to be the cause of severe postoperative bleeding in a patient also on antiplatelet agents [11]. Few other clinical studies have addressed this topic. The purpose of our study, therefore, was to assess the effects of ENOX on bleeding indices in patients undergoing CABG. Our hypothesis was that ENOX would increase transfusion rates and bleeding complications.

	Material and methods

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After approval by the institutional review board of the Wake Forest University School of Medicine, we completed a retrospective review of all patients undergoing isolated, first-time, elective CABG from July 1997 to May 2002. The study population included only patients who were receiving treatment doses of ENOX or a continuous infusion of UFH before surgery. Exclusion criteria included the following: (1) thrombocytopenia (defined as a platelet count of < 150,000), (2) hemophilia or any other disease state affecting hemostasis, (3) a history of heparin-induced thrombocytopenia, (4) repeat or emergent CABG, (5) off-pump coronary bypass procedures, (6) discontinuation of ENOX or heparin more than 24 hours before CABG, or (7) administration of both ENOX and heparin, except for operating room dosage, within 24 hours of CABG.

A total of 92 patients on preoperative ENOX met study criteria. These patients were divided into two groups: patients whose ENOX was discontinued more than 12 hours before surgery (ENOX > 12) and patients whose ENOX was discontinued less than 12 hours before surgery (ENOX < 12). Twelve hours represents approximately two half-lives of subcutaneously administered ENOX [12].

Because more than 300 patients were on preoperative UFH, a random sample of 110 of these patients was initially selected. From these 110, patients were further reviewed for the presence of exclusion criteria and the remaining chosen for the UFH group.

Preoperative data collected included baseline hematologic characteristics and medications. Data regarding the CABG procedure included the duration of cardiopulmonary bypass (CPB), the maximum activated clotting time achieved, the amount of protamine and aminocaproic acid administered, and the volume of blood products transfused intraoperatively. Hemoglobin and transfusion data collected included perioperative hemoglobin measurements as well as the quantity of red blood cells (RBC), fresh frozen plasma, or platelets administered intraoperatively and during the first 24 hours after surgery.

Unfractionated heparin infusions were discontinued upon entrance into the operating room. All CABG procedures were performed using standard techniques including general anesthesia, median sternotomy, central cannulation, CPB with moderate systemic hypothermia (28° to 32°C), blood cardioplegic arrest, shed blood return with cell-saver devices, and perioperative use of aminocaproic acid. Anticoagulation for CPB was achieved with an initial dose of UFH (300 U/kg) followed by subsequent titrated doses as needed to achieve an activated clotting time of longer than 480 seconds. Complete reversal of intraoperatively administered heparin was performed with protamine at an initial dose of 1 mg per 100 U UFH administered. No patient was maintained on UFH or ENOX postoperatively. An infusion of aminocaproic acid was continued postoperatively until chest tube output was less than 100 mL/h for 4 hours. A standard policy regarding the transfusion of blood or blood products is not in place at our institution and was dictated by physician preference.

Continuous data were compared between the three groups (UFH, ENOX > 12, ENOX < 12) using the Kruskal-Wallis one-way analysis of variance on ranks. Overall significance was further tested with the Dunn method for multiple comparisons. Nominal data were compared between the groups using the -square test. Data are expressed as mean ± standard deviation. A p-value of less than or equal to 0.05 was considered significant.

	Results

Top Abstract Introduction Material and methods Results Comment Conclusions Discussion References

 
A total of 69, 58, and 34 patients comprised the UFH, ENOX > 12, and ENOX < 12 groups, respectively. Demographics and comorbidities were similar among the groups (Table 1). The use of antiplatelet agents was also similar among the groups. Two patients in the UFH group had received the glycoprotein IIb/IIIa inhibitor, eptifibatide, within 8 hours of surgery. No patients in the ENOX > 12 or ENOX < 12 had received IIb/IIIa inhibitor within 72 hours. Preoperative hematologic data revealed a significantly lower platelet count in the UFH group consistent with the known greater antiplatelet effect of UFH compared with LMWH [13], as well as an expected higher partial thromboplastin time. Intraoperative data (Table 2) was similar among the groups except that the ENOX < 12 group received a significantly higher total dose of aminocaproic acid. One patient in the UFH group and 4 patients in the ENOX > 12 group received aprotinin instead of aminocaproic acid.

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusions Discussion References

The present study demonstrated lower perioperative hemoglobin values and higher transfusion rates when ENOX was given less than 12 hours before CABG. These risks were not significantly different from those associated with UFH when ENOX was discontinued more than 12 hours before CABG. These findings are consistent with the pharmacokinetics of ENOX that demonstrate an elimination half-life of 5 to 6 hours, but are inconsistent with a known, persistent anti-Factor Xa activity that can be as high as 30% of peak anti-Factor Xa activity at 12 hours [12]. In the present study, the nonsignificant increase in reoperation for bleeding in patients who received ENOX at any time preoperatively is troubling, especially in light of a confirmatory report [10]. This issue warrants further investigation.

Other formulations of LMWH have been used for ACS with varying effectiveness. In a study comparing the LMWH dalteparin with UFH, no significant differences between the rates of death or other cardiovascular end points were observed [16]. In a separate report, investigators found greater perioperative blood loss in patients undergoing CABG if dalteparin was administered within 12 hours of surgery [9]. Nadroparin, another LMWH, was associated with worse composite cardiovascular outcomes compared with UFH for ACS when used for 14 days after onset of symptoms, and similar outcomes to UFH when used for 6 days [17]. Taken together, these studies suggest that despite similar pharmacology, LMWHs have different clinical characteristics and cannot be equally substituted. These clinical differences also suggest that the findings of our study should not be extrapolated to other formulations of LMWH.

This study is limited by its relatively small size and retrospective nature. Despite the low numbers of patients, however, the preoperative data revealed fairly well-matched groups. Opportunities for clinically important Type II errors were present and included the similar outcomes for patients in the UFH and ENOX > 12 groups. A larger sample size in the ENOX > 12 group may have yielded statistical significance, because these patients did have a nonsignificant lower postoperative hemoglobin, higher transfusion rate, and higher rate of return to the operating room for bleeding. Therefore, our results cannot support the relative safety of surgery when ENOX has been discontinued for more than 12 hours beforehand. Additionally, this study cannot address potential factors that may reduce bleeding associated with ENOX such as the use of aprotinin or hemofiltration while on CPB. Finally, preoperative use of clopidogrel and long-acting platelet glycoprotein IIb/IIIa inhibitors are known to increase bleeding risks [18, 19], and would confound the results of any analysis on bleeding indices to an unknown degree. While these issues warrant further study, it is hoped that clinical wisdom will limit the number of patients undergoing nonemergent surgery while receiving a myriad combination of antiplatelet agents, anticoagulants, and other drugs that alter hemostasis.

	Conclusions

Top Abstract Introduction Material and methods Results Comment Conclusions Discussion References

 
In patients with ACS undergoing CABG, the preoperative use of ENOX less than 12 hours before surgery is associated with lower postoperative hemoglobin values and a higher risk of transfusion compared with continuous UFH. Preoperative use of ENOX may be associated with an increased risk of reoperation for bleeding. In patients with ACS, ENOX should be converted to a continuous infusion of UFH at least 12 hours before surgery.

	Discussion

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DR D. GLENN PENNINGTON (Johnson City, TN): This review was well done and, of course, one we are all interested in since virtually all of our patients seem to be taking some type of anticoagulant or antiplatelet drug and we are concerned about bleeding. I have several comments.

Several hundred people might have been eligible for your study over 5 years and yet only 90-something patients ended up in the trial, indicating, I think, that you may have already beaten the problem in your institution. Only 34 patients were on enoxaprin at less than 12 hours before surgery.

I guess the take-home message here, though, is if we could stop the Lovenox within 12 hours of surgery then bleeding problems are unlikely. The thing that bothers me a little bit, and you seem concerned about, is that even in the group in whom enoxaprin had been stopped more than 12 hours before surgery, the incidence of return to the operating room for bleeding was still increased. Eight percent of patients in the ENOX > 12 group also received clopidogrel, so I wonder if the clopidogrel was a contributing factor for those patients going back for more surgery?

Another question. It seems very clear we need to stop enoxaprin before 12 hours, but what about the 24 hours as you indicate the American Heart Association recommends? Would a longer interval between the last enoxaprin and the onset of surgery completely eliminate the bleeding problem?

I also would like to reiterate your point that all low-molecular-weight heparins are not the same and therefore these data cannot be automatically applied to other low-molecular-weight heparins.

A final question. You did exclude emergency cases here, but if you had to handle an emergency case and you knew the patient was on enoxaprin within 12 hours of surgery, are there any other measures you would carry out to stop the bleeding?

I thought your study was an important contribution. Thank you.

DR KINCAID: Thank you, Dr Pennington, for those comments and questions. Regarding your first comment on the low numbers of patients in this study, I have two explanations. The first is that an increasing number of our patients who have risk factors that contraindicate use of cardiopulmonary bypass, including higher risks of bleeding, undergo off-pump surgical procedures, which became a more common modality, especially in the later years of the study.

The second explanation, as you correctly identified, is that we do seem to have control over the situation at our institution, and our cardiologists are in acceptance with our desire to stop enoxaparin as soon as we anticipate the need for surgery.

Regarding your second question about the increased trend toward reoperation that we observed, this finding was also recently reported by the group at Latter Day Saints Hospital in Utah in which they found a statistically significant increased risk of reopening for patients on preoperative enoxaparin. They did not find an increased risk of transfusions or a decreased hemoglobin, however. A larger study in our hands would likely demonstrate the same statistically significant reopening rates.

Regarding the use of clopidogrel in 5 patients, the transfusion amounts in these patients was not overtly excessive compared with other patients in the study and unlikely affected the results.

Regarding your comments about other low-molecular-weight heparins, currently no other drugs in this category have demonstrated improved efficacy over unfractionated heparin in patients with acute coronary syndromes.

Lastly, regarding techniques that might benefit patients who need emergent surgery while on enoxaparin, one potential solution is to perform the operation off-pump if technically and hemodynamically feasible. The other potential method to combat bleeding would be use of hemofiltration or ultrafiltration while on pump, and these methods warrant further investigation.

DR JEROME M. MCDONALD (Ft. Lewis, WA): Thank you for that cogent presentation and addressing this important topic. Last year I and others at Washington University looked at this problem, also. As you noted, we had an increased blood product transfusion as well as reexploration in the patients on enoxaparin. One of the things that you mentioned that some colleagues are still questioning, and we noted also, is that the problem extends beyond the 12-hour interval that most cardiologists feel is the interval of concern. We found enoxaparin to be the strongest predictor of reexploration over clopidogrel or any of the other antiplatelet or anticoagulant medications. Did you look at any of the other antiplatelet or anticoagulant medications with regard to what was the strongest predictor of postoperative transfusion or reexploration?

DR KINCAID: Perioperative use of other anticoagulants and other antiplatelet agents was low in this study, including 5 patients on clopidogrel and 2 on IIb/IIIa inhibitors. Because of this low number, I do not think we can extrapolate any conclusions. I agree with your comments about the increased reopening rate in any patient who has been on preoperative enoxaprin, a finding that is consistent with the pharmacokinetics of enoxaparin demonstrating an approximately 30% anti-factor 10A activity at 12 hours. The persistence of this activity is also variable and is dependent on the preoperative duration of therapy, renal function, and patient size.

	References

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