BREAST

The Timing of Preoperative Prophylactic Low-Molecular-Weight Heparin Administration in Breast Reconstruction

Jerrod N. Keith, M.D. Tae W. Chong, M.D. Diwakar Davar, M.D. Alexander G. Moore, B.S. Alison Morris, M.D., M.S. Michael L. Gimbel, M.D.
Iowa City, Iowa; Dallas, Texas; and Pittsburgh, Pa.

Background: Venous thromboembolism continues to be problematic despite increased recognition and advancements in venous thromboembolism prophylaxis. Although migration toward preoperative chemoprophylaxis increases, plastic surgeons seem reticent to adopt this practice. This study evaluates preoperative enoxaparin administration in breast reconstruction patients. Methods: Patients undergoing breast reconstruction performed by a single surgeon over a 5-year period were evaluated retrospectively. The authors introduced preoperative chemoprophylaxis with enoxaparin in all breast reconstructions during this time. Prosthetic-based and microsurgical breast reconstructions were examined. Patients were divided into two groups: those who did and those who did not receive preoperative enoxaparin. The authors reviewed patient demographics, comorbidities, and complications, focusing on bleeding complications. Results: Three hundred patients (450 breasts) were included. One hundred fifty-four patients (244 breasts) underwent reconstruction with tissue expanders, and 146 (206 breasts) underwent free flap reconstructions. One hundred seventy-nine of 300 were given preoperative enoxaparin. Eleven hematomas occurred, eight (4.5 percent) in the enoxaparin group and three (2.5 percent) without enoxaparin (p = 0.399). Blood transfusions were given to four patients (2.2 percent) who received enoxaparin and one patient (0.8 percent) who did not (p = 0.652). Finally, any type of bleeding complication occurred in 11 patients (6.1 percent) with enoxaparin and in four (3.3 percent) without (p = 0.419). Larger breasts were more likely to receive enoxaparin (p = 0.011), which did not result in higher bleeding complications. Conclusion: In this retrospective study, the authors found that preoperative chemoprophylaxis in breast reconstruction was associated with an acceptable rate of postoperative bleeding complications. (Plast. Reconstr. Surg. 132: 279, 2013.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

enous thromboembolism continues to be problematic in plastic surgery despite increased recognition and advancements in venous thromboembolism prophylaxis. Venous thromboembolism affects an estimated 33,000 plastic surgery patients per year.1 Unfortunately,
From the Department of Surgery, Division of Plastic Surgery, University of Iowa Hospitals and Clinics; the Department of Plastic Surgery, University of Texas Southwestern Medical Center; and the Departments of Medicine and Plastic Surgery, University of Pittsburgh School of Medicine. Received for publication February 4, 2013; accepted F ebruary 26, 2013. Copyright 2013 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0b013e318295870e

despite risk-assessment model publicity in the plastic surgery literature,24 the specialty still lags behind other medical fields in providing adequate venous thromboembolism prophylaxis.57 American College of Chest Physicians venous thromboembolism prophylaxis guidelines are based on the most comprehensive, multispecialty, systematic reviews compiled from over 700

Disclosure: The authors have no financial interest in any of the products, devices, or drugs mentioned in this article. The authors have no relevant commercial associations or financial disclosures related to this article.

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references.8 Plastic surgery patients are included for the first time in the 2012 guidelines. The American College of Chest Physicians recommends chemoprophylaxis for general or abdominal-pelvic surgery patients scoring 3 or higher on the Caprini scale. Patients with breast cancer undergoing mastectomy and reconstruction generally fall into the high-risk group, with Caprini scores of 5 or greater. Thus, it is advisable that these patients receive perioperative mechanical prophylaxis and chemoprophylaxis. Although venous thromboembolism chemoprophylaxis is frequently administered postoperatively in the field of plastic surgery, other specialties take a more aggressive approach by administering prophylactic anticoagulants preoperatively. Recent studies in both bariatric surgery patients and gynecologic oncology patients support the safety of use of preoperative chemoprophylaxis in their respective high-risk patient populations.9,10 In addition, in a meta-analysis of 26 studies investigating the administration of preoperative chemoprophylaxis in cancer patients undergoing nonorthopedic surgical procedures, Leonardi et al. found a threefold decrease in thromboembolic complication rate.11 Although preoperative chemoprophylaxis would seem logical, as venous pooling and stasis begin on induction of anesthesia, surgeons are reticent to give preoperative anticoagulants because of the increased risk of surgical bleeding complications. The purpose of our study was to evaluate our experience with preoperative enoxaparin administration in breast reconstruction patients. Because of a change in clinical practice, we are able to compare two breast reconstruction patient cohorts; the first group did not receive preoperative chemoprophylaxis, whereas the second group did. Specifically, we address the question of whether preoperative enoxaparin is associated with an acceptable bleeding complication risk in this surgical population. very minor subset of our breast reconstruction cohort. All other breast reconstruction patients were included in the analysis. Types of reconstructions included prosthetic-based reconstruction with tissue expanders/implants and microsurgical breast reconstruction. Patients were divided into two groups: those receiving preoperative prophylactic enoxaparin and those not receiving preoperative prophylactic enoxaparin. We reviewed the following patient demographics and comorbidities: age, BRCA status, diabetes, smoking status, coronary artery disease, hypertension, chronic obstructive pulmonary disease/ asthma, autoimmune disease, prior breast cancer, body mass index, preoperative breast size (by bra cup size, defining small as less than a D cup and large as D cup or greater), neoadjuvant chemotherapy, and neoadjuvant radiation therapy. We collected the following operative and postoperative details: tissue expander pocket type (total muscle coverage or acellular dermal matrix assisted), acellular dermal matrix dimensions, tissue expander size and intraoperative fill volumes, estimated blood loss, antibiotic use and duration, drainage tube duration, and final expander fill volume. Finally, we collected the following perioperative complication data: hematoma, seroma, the need for blood transfusion, mastectomy flap complication, wound healing problem, infection, microvascular thrombosis, free flap failure, and venous thromboembolic events. Hematomas were defined as those requiring procedural interventions such as drainage or reoperation. Any bleeding complications were defined as those patients who encountered postoperative hematomas and/or blood transfusions. Statistical Analysis Patient characteristics including demographic, comorbidities, body mass index, and operative details were summarized and compared between patients receiving enoxaparin and those not receiving enoxaparin using t tests, Wilcoxon rank-sum, chi-square, or Fishers exact tests where appropriate, with a value of p < 0.05 considered significant. Bleeding complications including hematomas, transfusion, or any complication were compared by enoxaparin use using Fishers exact test in the cohort overall and in those having tissue expanders or free flaps.

PATIENTS AND METHODS

A retrospective review was performed of all patients undergoing breast reconstruction performed by a single surgeon over a 5-year period between October of 2006 and April of 2011. The senior surgeon (M.L.G.) gradually incorporated preoperative chemoprophylaxis in all breast reconstructions beginning in 2008. Institutional review board approval was obtained to perform this study. Latissimus dorsi and pedicled abdominal flap reconstructions were not included because they were so few that they represented a

RESULTS
Three hundred seventeen patients underwent breast reconstruction during the study period.

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Three hundred patients (450 breasts) were included in the study, and 17 were excluded based on type of reconstruction. Patient demographics are listed in Table1. Initially, no patients were given preoperative chemoprophylaxis. Over time, a change in practice pattern resulted in selected use, followed by uniform use, of preoperative enoxaparin (30mg) subcutaneously within 1 hour of incision. Enoxaparin was continued after surgery (40mg daily or 30mg twice daily) until the patient was ambulatory. Mechanical prophylaxis with sequential compression devices and early ambulation was used in all patients. Chemoprophylaxis was discontinued on discharge to home. Patients underwent tissue expander placement (n = 154), with either total muscular coverage (n = 32) or with the use of acellular dermal matrix (n = 122). Expanders were filled intraoperatively, with an average initial fill volume of 165 cc and an average final fill volume of 460 cc. Jackson-Pratt drains remained in place for an average of 13 days. One drain per mastectomy site was used for total mastectomies, and two drains per site were used for modified radical mastectomies. Microsurgical reconstructions (n = 146 patients, 206 breasts) included abdomen-based flaps (199 breasts), transverse upper gracilis flaps (six breasts), and a superior gluteal artery perforator flap (one breast). There was one free flap failure. Although there were no identified deep venous thromboses in any patients, one free flap patient who received preoperative enoxaparin developed an asymptomatic postoperative pulmonary embolism found incidentally on computed tomography of the abdomen for distention. Table2 lists procedural and enoxaparin results. The rate of bleeding complications was low. A total of 11 hematomas occurred in eight patients (4.5 percent) who received enoxaparin and in three (2.5 percent) who did not. Blood transfusions were given in four patients (2.2 percent) who received enoxaparin and in one patient (0.8 percent) who did not. Finally, any type of bleeding complication (hematomas plus transfusions) occurred in 11 patients (6.1 percent) who received enoxaparin and in four patients (3.3 percent) who did not (Table3). Because increased complications have been reported in reconstructions of women with large breasts,12 breast size was analyzed independently based on preoperative bra cup size . First, we examined whether there was bias in giving preoperative enoxaparin based on bra cup size. No significant difference in enoxaparin use was observed between the different breast cup size groups (p = 0.097). We then grouped the data into small and large breast size, in which small breasts were defined as less than D cup and large breasts were D cup or larger (Table 1). We found that larger breasts were statistically more likely to receive preoperative enoxaparin (p = 0.011). However, despite this increased use of enoxaparin, we found no statistical increase in rates of hematoma formation, blood transfusions, or any bleeding complications between the small and large breast groups. There was a trend for patients with hematomas to have a somewhat lower body mass index (mean SD body mass index, 23.1 3.5kg/m2 for hematomas versus 26.0 5.4kg/m2 for no hematoma, p = 0.07). Need for transfusion or presence of any bleeding complication was not related to body mass index (mean SD body mass index, 25.8 5.4kg/m2 for no transfusion versus 28.1 6.8kg/m2 for transfusion, p = 0.36; for any complication, 24.3 5.1kg/m2 versus 26.0 5.4kg/m2, p = 0.24). Because flap reconstructions have inherently larger dissected tissue surface areas and therefore

Table 1. Demographic Information, Patient Comorbidities, and Pertinent Patient Characteristics

No Enoxaparin (%) No. of patients Mean age, yr Mean BMI DM HTN CAD Asthma/COPD Smoker Previous breast cancer Neoadjuvant chemotherapy Previous irradiation Breast size (n = 290)  Small (<D cup) Large (D cup) 121 47.8 25 1 (0.8) 21 (17.3) 3 (2.5) 6 (5.0) 19 (15.7) 21 (17.3) 15 (12.4) 13 (10.7) 100 (85.5) 17 (14.5) Enoxaparin (%) 179 47.7 26 2 (1.1) 24 (13.4) 2 (1.1) 6 (3.3) 26 (14.5) 36 (20.1) 33 (18.4) 23 (12.8) 126 (72.8) 47 (27.2)) Total (%) 300 3 (1) 45 (15) 5 (1.7) 12 (4) 45 (15) 57 (19) 48 (16) 36 (12) 226 (77.9) 64 (22.1) p 0.959 0.303 0.809 0.332 0.394 0.553 0.749 0.657 0.253 1.000 0.011

BMI, body mass index; DM, diabetes mellitus; HTN, hypertension; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease.

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Table 2. Type of Reconstruction as Related to Use of Preoperative Enoxaparin Chemoprophylaxis
No Enoxaparin Tissue expander Free flap Total
*p = 0.761.

Enoxaparin 90 89 179

Total 154 (244 breasts) 146 (206 breasts) 300*

64 57 121

greater potential for bleeding, subset analyses of bleeding complication data were performed for the two types of reconstruction. No statistically significant difference in bleeding complications existed between patients who received preoperative enoxaparin and patients who did not in either the tissue expander subgroup (Table4) or the flap subgroup (Table5). Finally, we looked at all bleeding complications based on type of breast reconstruction performed, to determine whether the type of reconstruction played a role in bleeding complications. There were eight bleeding complications (5.4 percent) in the tissue expander group and seven (4.8 percent) in the free flap reconstruction group. This difference was not statistically significant (p = 1.00).

DISCUSSION
Breast cancer patients constitute a high-risk population for the development of perioperative venous thromboembolic complications. Risk factors in this population include underlying malignancy, presence of central venous catheters, hormone-modulating medications, chemotherapy, and, commonly, increased age.13,14 In addition, breast reconstruction involves operative times greater than 45 minutes, another risk factor for venous thromboembolism. Leonardi et al. performed a systematic review of deep venous thrombosis prophylaxis in cancer patients. They reviewed nonorthopedic surgery patients with cancer from 26 retrospective controlled trials encompassing 7639 patients. Most studies in the review gave the first chemoprophylactic dose 2 hours preoperatively, whereas some gave a dose

the night before. The overall deep venous thrombosis rate was 12.7 percent for pharmacologic prophylaxis compared with 35.2 percent in controls. Furthermore, the combination of heparin and mechanical prophylaxis decreased the rate to 5 percent in this high-risk population. Importantly, discontinuation of high-dose (>5000 units three times daily) heparin prophylaxis occurred in only 3 percent of patients secondary to bleeding.11,15 The results from the current study corroborate the acceptably low bleeding risk with preoperative chemoprophylaxis. Many surgical specialties are exploring the use of preoperative low-molecular-weight heparin for venous thromboembolism prophylaxis. Martino et al. retrospectively reviewed 122 gynecologic cancer patients, half of whom were given preoperative low-molecular-weight heparin and pneumatic compression devices. They found no difference in bleeding, transfusion requirements, operative time, or hospital stay.9 Furthermore, Singh et al. used body mass indexbased preoperative dosing in obese patients undergoing Roux-en-Y gastric bypass surgery. Some of these 170 patients received a dose as high as 60mg of enoxaparin preoperatively. They also found this regimen to be safe and effective in their high-risk patient population, reporting no clinically significant deep venous thrombosis or pulmonary embolism events during a 2-year follow-up.10 Hatef et al. examined the relationship between body contouring surgery and enoxaparin administration. They compared enoxaparin treatment timing, 2 hours preoperatively versus intraoperatively or immediately postoperatively. There was no statistically significant difference in bleeding requiring transfusions, intraoperative blood loss, or venous thromboembolic events.16 In the breast reconstruction literature, Liao et al. performed a multicenter study of 679 patients undergoing transverse rectus abdominis musculocutaneous (TRAM) and free TRAM flap operations. The found venous thromboembolism rates with and without postoperative chemoprophylaxis of 0.8 and 1.4 percent, respectively, and hematoma rates of 1 and 0.5 percent, respectively.17 Ashjian et al. compared postoperative aspirin

Table 3. Bleeding Complications as Related to Use of Preoperative Enoxaparin Chemoprophylaxis

No Enoxaparin (%) No. of patients Hematoma Blood transfusion Any bleeding complication 121 3 (2.5) 1 (0.8) 4 (3.3) Enoxaparin (%) 179 8 (4.5) 4 (2.2) 11 (6.1) Total (%) 300 11 (3.7) 5 (1.7) 15 (5.0) p 0.399 0.652 0.419

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Table 4. Bleeding Complications as Related to Use of Preoperative Enoxaparin Chemoprophylaxis in the Tissue ExpanderOnly Group
No Enoxaparin (%) No. of patients Hematoma Transfusion Any bleeding complication 58 2 (3.4) 0 2 (3.4) Enoxaparin (%) 90 5 (5.6) 2 (2.2) 6 (6.7) Total (%) 148 7 (4.7) 2 (1.4) 8 (5.4)

versus low-molecular-weight heparin after free flap surgery and found hematoma rates of 2.3 and 2.9 percent and pulmonary embolism rates of 1.2 and 1.6 percent, respectively.18 Our preoperative enoxaparin group hematoma rate (3.7 percent) was within the published norm of 0.5 to 5.7 percent.15,17,19 Importantly, the current study is not designed to determine a difference in venous thromboembolism between those receiving and those not receiving preoperative enoxaparin. The timing of chemoprophylaxis is the key issue. The critical thrombosis period begins at surgery and can continue beyond hospitalization.20 One must weigh the risk of bleeding complications with early prophylaxis administration against the risk of venous thromboembolism.20 Pannucci et al. studied autogenous breast reconstruction and venous thromboembolism, finding an overall venous thromboembolism rate of 2.2 percent. However, only 11.8 percent of the total patient population received any form of pharmacologic prophylaxis. Of these patients, three of 20 who received postoperative chemoprophylaxis developed venous thromboembolism, whereas none was seen in those patients receiving preoperative prophylaxis.21 In a study by Kim et al., two groups of patients undergoing immediate pedicled TRAM flap breast reconstruction were compared, with one group receiving no chemoprophylaxis and the other receiving 7 days of enoxaparin starting 1 hour preoperatively. They found no difference in transfusion rates, hematomas, or seromas. However, there was a significant difference in asymptomatic pulmonary embolism, 16.7 percent in the group without chemoprophylaxis versus 0 percent in the group receiving preoperative and postoperative chemoprophylaxis.19 The current study identified one patient who developed an asymptomatic,

incidentally found pulmonary embolism after free flap breast reconstruction. This low rate may stem from the fact that our patients are studied (chest computed tomographic angiography or lower extremity duplex sonography) only if symptomatic. It is well accepted that many venous thromboembolisms are asymptomatic and often not discovered without routine imaging of high-risk patients.22 Overall, our study compares favorably with the reported literature, as the venous thromboembolism rates were very low and complication rates were within the acceptable range. It was interesting to note the increased use of enoxaparin in patients with larger breast size. This may have been attributable to some biased use of enoxaparin because of perceived increased venous thromboembolism risks in patients who were viewed as having a larger body habitus. However, for the purposes of this study, it is more important to note that the increased use of preoperative enoxaparin in patients with large breasts did not result in increased bleeding complications. We did notice a trend toward increased bleeding complications in those patients receiving enoxaparin. The current study has 80 percent power to detect a fourfold difference in bleeding complications. Although a larger study might have found the bleeding complication rate difference observed in our study to be statistically significant, the authors feel that a relatively small increase in readily treatable bleeding complications is outweighed by the potential benefits of decreased venous thromboembolism complications demonstrated in the current surgical literature. Our study is also limited by its retrospective nature. This study is not intended or powered to demonstrate the benefit of chemoprophylaxis in preventing venous thromboembolism complications,

Table 5. Bleeding Complications as Related to Use of Preoperative Enoxaparin Chemoprophylaxis in the Free FlapOnly Group
No Enoxaparin (%) No. of patients Hematoma Transfusion Any bleeding complication 58 1 (1.7) 1 (1.7) 2 (3.4) Enoxaparin (%) 89 3 (3.4) 2 (2.2) 5 (5.6) Total (%) 146 4 (2.7) 3 (2.0) 7 (4.8)

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as multiple other studies have already established this point. However, it does show that the bleeding complication rates with preoperative chemoprophylaxis were within the acceptable range in prosthesis-based and microsurgical autologous tissuebased breast reconstruction.
9. Martino MA, George JG, Chen CC, et al. Preoperative enoxaparin is safe to use in major gynecologic surgery for prophylaxis of venous thromboembolism: A retrospective cohort study. Int J Gynecol Cancer 2012;22:681685. 10. Singh K, Podolsky ER, Um S, et al. Evaluating the safety and efficacy of BMI-based preoperative administration of low-molecular-weight heparin in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg. 2012;22:4751. 11. Leonardi MJ, McGory ML, Ko CY. A systematic review of deep venous thrombosis prophylaxis in cancer patients: Implications for improving quality. Ann Surg Oncol. 2007;14:929936. 12. Lanier ST, Wang ED, Chen JJ, et al. The effect of acel lular dermal matrix use on complication rates in tissue expander/implant breast reconstruction. Ann Plast Surg. 2010;64:674678. 13. Geerts WH, Bergqvist D, Pineo GF, et al.; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines (8th Edition). Chest 2008;133(Suppl):381S453S. 14. Lyman GH, Khorana AA, Falanga A, et al.; American Society of Clinical Oncology. American Society of Clinical Oncology guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:54905505. 15. Leonardi MJ, McGory ML, Ko CY. The rate of bleeding com plications after pharmacologic deep venous thrombosis prophylaxis: A systematic review of 33 randomized controlled trials. Arch Surg. 2006;141:790797; discussion 797. 16. Hatef DA, Kenkel JM, Nguyen MQ, et al. Thromboembolic risk assessment and the efficacy of enoxaparin prophylaxis in excisional body contouring surgery. Plast Reconstr Surg. 2008;122:269279. 17. Liao EC, Taghinia AH, Nguyen LP, Yueh JH, May JW Jr, Orgill DP. Incidence of hematoma complication with heparin venous thrombosis prophylaxis after TRAM flap breast reconstruction. Plast Reconstr Surg. 2008;121:11011107. 18. Ashjian P, Chen CM, Pusic A, Disa JJ, Cordeiro PG, Mehrara BJ. The effect of postoperative anticoagulation on microvascular thrombosis. Ann Plast Surg. 2007;59:3639; discussion 39. 19. Kim EK, Eom JS, Ahn SH, Son BH, Lee TJ. The efficacy of prophylactic low-molecular-weight heparin to prevent pulmonary thromboembolism in immediate breast reconstruction using the TRAM flap. Plast Reconstr Surg. 2009;123:912. 20. Warwick D, Rosencher N. The critical thrombosis period in major orthopedic surgery: When to start and when to stop prophylaxis. Clin Appl Thromb Hemost. 2010;16:394405. 21. Pannucci CJ, Chang EY, Wilkins EG. Venous thromboem bolic disease in autogenous breast reconstruction. Ann Plast Surg. 2009;63:3438. 22. Geerts WH, Jay RM, Code KI, Chen E, Szalai JP, Saibil EA, Hamilton PA. A comparison of low-dose heparin with lowmolecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med. 1996; 335:701707.

CONCLUSIONS
To date, this is the largest study looking at preoperative chemoprophylaxis in breast reconstruction. Preoperative enoxaparin was found to be acceptable to use in our patient population undergoing prosthesis-based and microsurgical breast reconstruction.
Michael L. Gimbel, M.D. 5750 Centre Avenue, Suite 180 Pittsburgh, Pa. 15206 gimbelml@upmc.edu

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