Low molecular-weight heparin for thromboprophylaxis in patients undergoing gastric cancer surgery: an experience from one Korean institute

Venous thromboembolism (VTE) is related to various risk factors such as cancer, peripheral vascular disease, heart disease, immobile condition, and recent history of major abdominal or orthopedic surgery [1, 2]. Among these, the presence of malignant disease significantly increases the risk of developing VTE. Therefore, hospitalized cancer patients undergoing chemotherapy or surgery appear to have the greatest risk of developing VTE [3]. In particular, patients with gastric, pancreatic, hematologic, and ovarian cancers have the greatest risks of developing VTE. Gastric cancer is associated with the fifth-highest rate of VTE [4]. A retrospective cohort study reports that the rate of VTE is 7.4% among patients with gastric cancers [5]. The American Society of Clinical Oncology VTE Guideline Panel recommends that physicians consider pharmacological thromboprophylaxis in patients undergoing major surgery for malignant disease [6]. Low-molecular-weight heparin (LMWH) has become a standard pharmacological agent for preventing VTE because it is easy to use, just once a day injection schedule.

Little study has published about the LMWH prophylaxis on patients with cancer surgery. Jeong et al. [7] reported that pharmacological thromboprophylaxis with LMWH is associated with a significant risk of bleeding complications.

The present study analyzed outcomes of LMWH prophylaxis during the gastric cancer surgery, and tried to compare with the outcomes of intermittent pneumatic compression (IPC) device without LMWH.

From July to October 2011, we reviewed 108 patients' medical records; diagnosed with histologically confirmed primary gastric adenocarcinoma, and who showed no evidence of distant metastasis upon preoperative evaluation. The patients divided into two groups: LMWH + IPC (group A) and IPC alone (group B). Use of enoxaparin depended on the surgeon's preference. We had two gastric surgeons in our hospital during this study, and only one surgeon (K.Y.S.) used enoxaparin. The Institutional Review Board of Seoul St. Mary's Hospital approved this study.

All patients had curative intent (R0) gastrectomy with extragastric lymph node dissection. We screened all patients' coagulation profiles, including bleeding time, prothrombin time, activated partial thromboplastin time, and platelet count. In order to screen the disease conditions related to hypercoagulability or bleeding tendency, the levels of protein C, protein S, antithrombin, homocysteine, factor Va, and antiphospholipid IgG/IgM were determined. All patients were managed by the critical pathway protocol; based on this, patients were encouraged to walk early on postoperative day 1 and resume diet no later than postoperative day 3.

The American College of Chest Physicians guidelines for thromboprophylaxis classify cancer surgery as a "high-risk" procedure for the development of VTE and recommend active prophylaxis including LMWH or unfractionated heparin [9]. The estimated incidences of deep vein thrombosis (DVT) and fatal PE in this group are 20%-40% and 0.4%-1.0% respectively [6, 9]. However, in Korea, the routine use of LMWH to prevent VTE in preoperative periods was not common. Surgeons are afraid of risks of unexpected intraoperative or postoperative bleeding. Many Korean surgeons are more concerned about the postoperative bleeding than prevention of rare risk of VTE with LMWH, compared with the high incidence of VTE in the western countries [10, 11].

The rate of thromboprophylaxis with LMWH is significantly lower in Asian countries than that in the Western countries because the true incidence and risks of VTE after cancer surgery in Asian patients remain uncertain. The incidence of VTE in Asian patients was approximately 3- to 5-fold lower in a previous report, although the incidence of asymptomatic VTE may be higher without thromboprophylaxis. An increased risk of postoperative bleeding is another issues related to LMWH usage.

Meta-analyses and randomized controlled trials conducted in the West revealed little or no increase in the rates of clinically significant postoperative bleeding with the use of prophylactic doses of LMWH [12-15]. However, few studies have evaluated the feasibility of LMWH prophylaxis in Asia. We are planning to determine the optimal thromboprophylaxis method during gastric cancer surgery. Before starting a prospective clinical trial, we tried to evaluate the safety of using LMWH in the present study. The LMWH tended to increase the risk of postoperative bleeding in patients with gastric cancer in our patients. However, most of the bleeding complications were minor events unrelated to mortality and mostly managed conservatively.

The surgical procedures and extent of surgery might influence bleeding risks, such as open versus laparoscopy and extent of lymph node dissection. Extensive lymph node dissection, which could increase the risk of bleeding complications, is a routine procedure for radical gastrectomy in Korea in contrast to surgery in the West [16]. Nonetheless, there was no significant difference in bleeding episodes with respect to the resection type, extent of lymph node dissection, or type of surgical approach (i.e., laparoscopic and open) between groups. Only high BMI was an independent risk factor for an increased risk of bleeding, probably because the surgical plane is more difficult to find and more friable for dissection in obese patients [17].

In order to examine the hypercoagulability status of Korean patients, we measured protein C, protein S, antithrombin, homocysteine, factor Va, and antiphospholipid IgG/IgM levels, which are well-known factors related to hypercoagulability. Interestingly, most factors were within normal limits, implying that hereditary causes of coagulopathy are not prominent among Korean patients. On postoperative day 1, 50 patients (46.2%) exhibited elevated D-dimer levels; of these patients, 3 (2.7%) who presented with asymmetric leg swelling underwent duplex ultrasonography to rule out DVT. None of these patients showed DVT.

The risk of bleeding associated with LMWH usage is hypothetically dependent on several factors including LMWH dosage and injection timing. A previous intervention study comparing the administration of 2,500 and 5,000 U LMWH in general surgical patients revealed that the incidence of DVT was significantly lower in those administered 5,000 U; however, the incidence of bleeding was significantly higher in these patients than that in patients administered 2,500 U [18]. In the present study, we used 40 mg of enoxaparin sodium, which recommended dosage in the previous trials [19, 20]. We just followed this dosage, which is sufficient to prevent VTE and to have reasonable rate of bleeding complications in Korean patients, but in future trial will also confirm it.

In this study, LMWH seems to increase bleeding risks, but it does not significantly alter the patients' clinical course. LMWH seemed to have a tendency to increase the risks of bleeding in patients with high BMI.

In Asia, due to the low-reported incidence of VTE, surgeons in Asia rather not interested in VTE prophylaxis as in Western surgeons. However, the patients' population were aged and got overweight. The real incidence of VTE or LMWH related risks of bleeding were uncertain.

Based on this study, we will launch a prospective randomized clinical trial to investigate the clinical efficacy of LMWH thromboprophylaxis by comparing LMWH plus IPC prophylaxis with IPC alone in Korean gastric cancer patients after surgery.