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Ann Thorac Surg 2005;80:518-522
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Early Postoperative Use of Unfractionated Heparin or Enoxaparin is Associated with Increased Surgical Re-Exploration for Bleeding

^a Cardiovascular Department, LDS Hospital, Salt Lake City, Utah
^b Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, Minnesota

Accepted for publication February 1, 2005.

^_* Address reprint requests to Dr Muhlestein, Cardiovascular Department, LDS Hospital, 8th Ave & C St, Salt Lake City, UT 84143 (Email: ldbmuhle{at}ihc.com).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: A variety of indications (eg, prosthetic heart valves, atrial fibrillation, etc.) exist for the use of unfractionated heparin (UFH) and enoxaparin (ENOX) in the early postoperative period following open-heart surgery. However, the overall postoperative risk for hemorrhage from the use of UFH and ENOX are not known.

METHODS: From 1998 to 2001, 2,977 consecutive open-heart or valve surgery patients were retrospectively evaluated. Postoperatively, 2,037 received no UFH or ENOX, 579 received intravenous UFH, and 361 received ENOX. Baseline characteristics were collected, patients who required surgical re-exploration for postoperative bleeding and time between surgery and re-exploration were followed-up.

RESULTS: Average patient ages were 64 ± 13, 65 ± 12, and 68 ± 10 years receiving none, UFH (p < 0.01 vs none), and ENOX (p < 0.01 vs none; p < 0.01 vs UFH), respectively. Rates of surgical re-exploration were 2.7% for none, 7.8% for UFH, and 8.9% for ENOX (vs none, adjusted hazard ratio = 2.8; p < 0.001 for UFH; hazard ratio = 3.3; p < 0.001 for ENOX). Males were also at higher risk for re-exploration (hazard ratio = 1.4; p = 0.07). For those requiring re-exploration, the interval between surgery and first re-exploration was prolonged (> 4 days) among those receiving ENOX (37.5%, odds ratio = 36.7; p = 0.001) and UFH (20.0%, odds ratio = 14.7; p = 0.01) compared with none (1.8%). Prolonged times with ENOX had a greater proportion of prolonged times than UFH (odds ratio = 2.5; p = 0.09).

CONCLUSIONS: Early postoperative use of ENOX and UFH is associated with a significant increase in re-exploration for postoperative bleeding, often at a significantly delayed time period after the initial surgery. This delay was especially common with ENOX suggesting the need for prospective studies.

	Introduction

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This article has been selected for the open discussion forum on the CTSNet Web Site: http://www.ctsnet.org.discuss

 

In a variety of conditions associated with patients undergoing open-heart surgery, early postoperative anticoagulation may provide clinical benefit. These include such conditions such as atrial fibrillation, prosthetic heart valves, left ventricular thrombus, and recurrent pulmonary emboli. Intraoperative heparin, the standard anticoagulant used in patients undergoing open-heart surgery, is usually given at fairly high doses, but then reversed immediately after surgery [1, 2]. It is also often the anticoagulant chosen for any necessary postoperative anticoagulation [3–6]. However, the postoperative continued use of heparin may carry an increased risk of bleeding complications.

Low-molecular-weight heparin has several potential advantages in comparison with unfractionated heparin (UFH). The low-molecular-weight heparins are easy to administer, have a predictable anticoagulant effect to allow accurate dosing, are resistant to activated platelets, and have a lower incidence of heparin-induced thrombocytopenia [7]. The use of enoxaparin (ENOX), a low-molecular-weight heparin, has been shown to be equivalent or superior to UFH in a variety of clinical situations including acute coronary syndrome [8–10] and deep venous thrombosis prophylaxis [11]. Therefore, it is possible that in the circumstance of anticoagulation postoperative open heart surgery, ENOX may be preferred over UFH.

However, although ENOX has apparent advantages over UFH, a recent study from our institution suggests that immediate preoperative use of ENOX in acute coronary syndrome patients getting ready to have coronary artery bypass grafting may result in a greater likelihood of returning to the operating room for re-exploration for postoperative hemorrhage [12]. This increased risk of bleeding is believed to be due, at least in part, to the prolonged half-life of ENOX, and the incomplete reversal of the effect of protamine. However, the risk for hemorrhage associated with postoperative administration of either UFH or ENOX has not been fully established. The primary objective of this study was to evaluate the effect of postoperative anticoagulation, using either UFH or ENOX, on the need to return for surgical re-exploration for postoperative bleeding.

	Patients and Methods

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Study Population
Between January 1997 and March 2001, all patients (n = 2,977) undergoing open-heart surgery for coronary artery bypass grafting and or valve surgery at LDS Hospital in Salt Lake City were retrospectively studied. Institutional Review Board submission was performed and granted approval to conduct this observational study between the identified dates. Six cardiovascular surgeons with a primary practice at LDS Hospital performed all operations. LDS Hospital is a teaching facility and utilizes fellows during open-heart procedures. This study was performed as a quality improvement initiative, but it was operated under the guidelines of the Declaration of Helsinki.

Study Variables
Baseline demographic variables were recorded for each patient and included patient age, gender, coexistent use of any anti-platelet therapy including aspirin, clopidogrel, ticlopidine, the IIb/IIIa inhibitors abciximab, eptifibatide, or tirofiban, and preoperative or postoperative use of warfarin, UFH or ENOX. Type and length of each surgical procedure were recorded. Procedures were categorized as coronary artery bypass grafting only, valve surgery only, or both (coronary artery bypass grafting and valve). Outcome variables were also recorded and included the return to the operating room for surgical re-exploration due to bleeding, the length of time between the initial procedure and re-exploration, the maximum measured perioperative partial thromboplastin time, and the receipt of packed red blood cells or platelet products.

Statistical Considerations
Statistical analysis was performed using SPSS for Windows (SPSS Inc., Chicago, IL). Descriptive statistics were calculated for the postoperative anticoagulation factors and for each co-variable included in the study. Baseline patient characteristics were compared between the anticoagulant groups using the Pearson ² test statistic for categorical variables and one-way analysis of variance for continuous variables. The proportion of patients returning to surgery within the first 3 days afterward was compared with the proportion returning after 4 or more days through the use of univariate logistic regression analysis and odds ratios calculated. A threshold of 4 days or more was chosen based on the assumption that a majority of postoperative bleeding complications in patients undergoing open-heart surgery without postoperative anticoagulation will occur within 3 days [12].

Univariate comparisons of the various baseline characteristics and other study co-variables to the primary outcome were performed using the Pearson’s ² test and analysis of variance as appropriate. Cox regression was then used to evaluate the effect of postoperative ENOX on the time interval until the patient returned to surgery or was discharged from the hospital while simultaneously controlling for the co-variables of age, gender, type of preoperative and perioperative anticoagulant received (none, UFH, ENOX), warfarin, and the five antiplatelet therapies. Hazard ratios (HR) and 95% confidence intervals (CI) are provided from these analyses.

	Results

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Of the 2,977 patients studied, 2,037 patients received no postoperative UFH or ENOX, 579 received intravenous UFH, and 361 received ENOX at some point during their postoperative hospitalization. Average patient age was 63.5 ± 13.1, 65.3 ± 12.3, and 68.3 ± 10.7 years among those receiving no postoperative UFH or ENOX, UFH (p = 0.003 vs none), and ENOX (p < 0.001 vs none, vs UFH), respectively. Furthermore among these groups, 75%, 63% (p < 0.001 vs none), and 62% (p < 0.001 vs none) were male. Other baseline characteristics are outlined in Table 1.

For those patients requiring re-exploration, the interval between the primary surgery and the first re-exploration was more frequently at a prolonged time (> 4 days) among those receiving ENOX (37.5%, OR = 36.7; p = 0.001) and UFH (20%; OR = 14.7; p = 0.01) compared with none (1.8%), with ENOX trending toward having more patients returning after the prolonged period even than UFH (OR = 2.5; p = 0.09). Median times to return to surgery were 7 hours for no UFH or ENOX, 19 hours for UFH (p < 0.001 vs no UFH or ENOX), and 41 hours for ENOX (p < 0.001 vs no UFH or ENOX; p = 0.20 vs UFH). Younger age also tended to predict later re-exploration (OR = 0.97 per year; p = 0.07).

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
First, the major findings of this study are that early postoperative use of UFH or ENOX are associated with a greater risk of surgical re-exploration for postoperative hemorrhage in patients receiving open-heart surgery. Second, patients receiving UFH or ENOX have a prolonged period of risk for surgical re-exploration in comparison with patients not receiving anticoagulation. Third, both the risk of surgical re-exploration and the prolonged period of this bleeding risk tended to be worse with use of ENOX in comparison with UFH.

Perioperative uses of UFH or ENOX are common in patients undergoing open-heart surgery. Both low-molecular-weight heparin and UFH have been shown to be effective in reducing thrombotic events in patients presenting with unstable angina or non-Q-wave myocardial infarction [8–10]. Heparin is also administered at high doses during open-heart surgery requiring cardiopulmonary bypass (CPB) [13–15], but it is commonly reversed immediately after the procedure. In addition, a variety of indications (eg, presence of prosthetic heart valves, atrial fibrillation, ventricular thrombus, prevention of deep venous thrombosis) may warrant the use of UFH or ENOX in the early postoperative period. Furthermore, in some circumstances, a postoperative coagulopathy may develop secondary to CPB that activates both the intrinsic and extrinsic coagulation pathways and may prompt early anticoagulation in order to prevent postoperative thrombotic morbidity [13]. Thus, both potential clinical benefits and hemorrhagic risks from postoperative anticoagulation therapy must be considered in patients undergoing cardiac surgery.

Although much is known about the potential indications for the use of postoperative UFH or ENOX in open-heart surgery, the overall risk a hemorrhage and the comparative risks between UFH and subcutaneous ENOX have not been as well defined. Our study suggests that both UFH and ENOX are associated with an increased incidence of re-exploration for postoperative bleeding. These findings are consistent with studies that reported excessive chest tube drainage when ENOX was substituted for UFH secondary to heparin-induced thrombocytopenia [16, 17].

Surgical re-exploration after open-heart surgery typically results from increased chest tube drainage, a fall in hematocrit or clinical instability, or both. Unfractionated heparin and ENOX may increase this risk, and they may also prolong the period of risk for re-exploration. Both the requirement for re-exploration and the prolonged intervals to the procedure represent increased hospital resource utilization, especially an increased use of both intensive care unit and hospital beds. Other cost variables such as the operating room, perfusion, anesthesia, blood bank, laboratory tests, respiratory therapy, and additional pharmacy demands are typically involved as well [18, 19]. Cost containment, particularly in the context of an aging population is necessary in an era of economically constrained health care systems.

Therefore, on the surface, it may appear that early postoperative use of UFH or ENOX should be avoided whenever possible after open-heart surgery. However, in certain circumstances, the clinical benefit arising from the use of postoperative anticoagulation may significantly outweigh the associated increased bleeding risk. Unfortunately, there are very limited studies documenting the clinical benefit of early anticoagulation in such circumstances as postoperative atrial fibrillation or left ventricular thrombus. Randomized trials under a variety of clinical circumstances may be necessary to clarify these important clinical questions.

As previously reported, postoperative anticoagulation, especially with ENOX, was associated both with an increased risk of surgical re-exploration and a prolonged interval of risk after open-heart surgery. Whether this is a reflection of the prolonged half-life of ENOX in comparison with UFH or due to a generally higher level of anticoagulation with presently used doses of ENOX is unknown. The standard therapeutic dose of ENOX is 1 mg/kg given subcutaneously twice per day. This dose was arrived at mainly from studies such as the TIMI-11a study [20] in which the highest safe dose was chosen, not the lowest effective dose. It is possible, in the setting of an increased risk of bleeding, such as early after open-heart surgery, that a lower dose may be both safe and effective. This will need to be determined in further studies. Currently it appears prudent to use postoperative anticoagulation after open-heart surgery only when the clinical indication is strong, and to use UFH as the agent of choice.

Our observations should be interpreted in the light of limitations imposed by a retrospective study design. All the information was obtained from original hospital records at LDS Hospital. However, it was not possible to collect information regarding all potential baseline confounding variables. A multivariate model was used to minimize the effect of known potential baseline differences. Selection of the study patients and the control population was not random, but the inclusion of consecutive patients should reduce selection bias. Also, differences in individual surgeons’ thresholds for the use of blood products, such as platelets, may have contributed to differences in the need to return to surgery for postoperative bleeding.

An interesting and unexpected finding in this study was the reduced rate of reoperation among patients treated with anti-platelet agents, mainly aspirin. Although this study does not provide enough information to explain this finding, it does raise the question as to whether some level of platelet inhibition during cardiopulmonary bypass may be protective to the platelets allowing them to survive their time in the oxygenator such that they remain available to participate in postoperative hemostasis.

After open-heart surgery, the use of any anticoagulant resulted in a significant increase in the incidence of re-exploration for postoperative bleeding and a significant increase in time to re-exploration, complications that directly affect hospital resource utilization. Also, the proportion of patients who had a significantly prolonged period of bleeding risk appeared to be greater for ENOX recipients than for UFH. Further prospective and randomized studies are required to ascertain the relative benefit versus risk associated with the use of early anticoagulation with either ENOX or UFH after open-heart surgery under a variety of clinical circumstances.

	References

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