Safety of postoperative thromboprophylaxis after major hepatobiliary pancreatic surgery in Japanese patients

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1 DOI 0.007/s ORIGINAL ARTICLE Safety of postoperative thromboprophylaxis after major hepatobiliary pancreatic surgery in Japanese patients Hiroki Hayashi Takanori Morikawa Hiroshi Yoshida Fuyuhiko Motoi Takaho Okada Kei Nakagawa Masamichi Mizuma Takeshi Naitoh Yu Katayose Michiaki Unno Received: 22 March 203 / Accepted: 20 August 203 Ó Springer Japan 204 Abstract Background and purpose Thromboprophylaxis is recommended for preventing postoperative venous thromboembolism (VTE) after abdominal surgery; however, its use after major hepatobiliary pancreatic surgery is typically avoided as it increases the risk of bleeding. We conducted this study to evaluate the safety of thromboprophylaxis after major hepatobiliary pancreatic surgery. Methods We analyzed the rates of postoperative bleeding, VTE, morbidity, and prolonged hospital stay in 349 patients who underwent major hepatobiliary pancreatic surgery, such as pancreaticoduodenectomy, hemihepatectomy or greater, and hepatopancreaticoduodenectomy. Results Chemical thromboprophylaxis was associated with significantly increased rates and risks of overall bleeding events vs. no chemical thromboprophylaxis (26.6 vs. 8.5 %, respectively). The rate of minor hemorrhage was significantly higher in patients who received chemical thromboprophylaxis (2.7 vs. 3.5 %); however, there were no differences in the rate of major hemorrhage requiring blood transfusion or hemostatic intervention between the groups (4.8 vs. 4.9 %). The postoperative VTE rate was also significantly decreased by chemical thromboprophylaxis (2.9 vs. 7.7 %). However, chemical thromboprophylaxis did not affect the rate of SSI, severe morbidity, or duration of the postoperative hospital stay. H. Hayashi (&) T. Morikawa H. Yoshida F. Motoi T. Okada K. Nakagawa M. Mizuma T. Naitoh Y. Katayose M. Unno Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Hospital, -, Seiryo-machi, Aoba-ku, Sendai , Japan hiroki@surg.med.tohoku.ac.jp Conclusion We consider that chemical thromboprophylaxis is beneficial and can be safely used even after major hepatobiliary pancreatic surgery. Keywords Postoperative venous thromboembolism (VTE) Thromboprophylaxis Hepatobiliary pancreatic surgery Introduction In Japan, pharmacological thromboprophylaxis has been adopted for the prevention of postoperative venous thromboembolism (VTE) after abdominal surgery, based on recent guidelines [, 2] and approval. However, many surgeons are reluctant to give patients chemical thromboprophylaxis after major hepatobiliary pancreatic surgery, such as pancreaticoduodenectomy (), hemihepatectomy or greater with caudate lobectomy (), and extrahepatic bile duct resection and hepatopancreaticoduodenectomy (), when performed simultaneously, because of the risk of bleeding complications. Hepatobiliary pancreatic surgeons generally perform radical, long operations on elderly cancer patients at high risk for postoperative VTE, with Caprini scores [3] of 5 or more. However, some studies have demonstrated a high incidence of postoperative VTE [4] after pancreatectomy and hepatectomy, concluding that chemical thromboprophylaxis should be given even after hepatectomy [5, 6] While pharmacologic thromboprophylaxis after abdominal surgery is commonly accepted, few reports have examined the safety and efficacy of this therapy following major hepatectomy or pancreaticoduodenectomy [7, 8]. Thus, we conducted this study to evaluate the safety and efficacy of chemical thromboprophylaxis by analyzing the risk of postoperative

2 hemorrhage and VTE in patients undergoing major hepatobiliary pancreatic surgery. We also analyzed the risk of postoperative morbidity, such as that from hepatic failure, pancreatic fistula, and surgical cite infection (SSI), as well as the length of the postoperative hospital stay. Materials and methods Thromboprophylaxis Since January 2009, we have administered enoxaparin or fondaparinux for postoperative chemical thromboprophylaxis. All the patients wore elastic stockings (ES) and had intermittent pneumatic compression (IPC) as the mechanical VTE prevention protocol. The chief surgeon decided on whether to give each patient chemical thromboprophylaxis. Enoxaparin and fondaparinux were used differently in the two periods of this study. Enoxaparin was administered at a dose of 4000 IU/day, and fondaparinux, at 2.5 or.5 mg/day. Although.5 mg/day of fondaparinux is a low-dose regimen for patients with impaired renal function (CCr \30 mg/min), this dose was prescribed by the chief surgeon, even for patients with normal renal function because of the perceived risk of postoperative hemorrhage. In the early period of this study, from January 2008 to December 2008, 85 patients were not given chemical thromboprophylaxis and treated only with mechanical thromboprophylaxis; from January 2009 to June 2009, 5 patients were given 2.5 mg/day of fondaparinux; from July 2009 to June 200, 66 patients were given 4000 IU/day of enoxaparin; and from July 200 to December 20, 75 and 48 patients, respectively, were given 2.5 and.5 mg/day of fondaparinux. The number of patients who did not receive any chemical thromboprophylaxis in each of the three groups since January 2009, was 20, 4, and 3, respectively. These patients did not receive chemical thromboprophylaxis, because the chief surgeon thought the possibility of postoperative hemorrhage was too great, especially for those with massive bleeding during the operation or poor coagulating activity due to low hepatic function after major hepatectomy. Interestingly, there were no significant differences in perioperative characteristics or in preoperative coagulation activity and platelet cells count between these 47 patients and those who received chemical thromboprophylaxis. The first dose of enoxaparin was administered either at 7:00 or 9:00, at least 24 h after the completion of surgery. Enoxaparin was administered repeatedly at 2-h intervals until 2:00 on postoperative day (POD) 8. The first dose of fondaparinux was administered either at 0:00 or 2:00, at least 24 h after the completion of surgery. If the first administration was at midnight, the second administration was at 2:00; that is, after 2 h. Fondaparinux was thereafter administered daily at 2:00 until POD 8. Most patients had an epidural catheter inserted, which was removed at 7:00 on POD 5, 0 h after and 2 h before enoxaparin administration, or at 9:00, 2 h after and 3 h before fondaparinux administration. Operative procedures Major hepatobiliary pancreatic surgery was defined as pancreaticoduodenectomy, hemihepatectomy or greater with caudate lobectomy, and extrahepatic bile duct resection and hepatopancreaticoduodenectomy. Patients, who underwent hemihepatectomy or greater, without extrahepatic bile duct resection, for HCC or metastatic liver cancer, were excluded from this study because such procedures are rare in our department. Patients A total of 360 patients underwent major hepatobiliary pancreatic surgery in our institute between January 2008 ( year before the introduction of postoperative pharmacologic prophylaxis) and December 20. We excluded patients from the analysis because drugs other than enoxaparin and fondaparinux were used for pharmacologic thromboprophylaxis. Thus, 349 patients who received enoxaparin, fondaparinux, or no chemical thromboprophylaxis were analyzed in this study. All patients were of Japanese ethnicity. Assessments Patients were checked for signs of postoperative hemorrhage during daily rounds in the hospital. Hemorrhage requiring RCC transfusion or hemostasis with surgery or IVR was defined as major hemorrhage and all other bleeding was defined as minor hemorrhage. All patients underwent routine computed tomography (CT) from the neck to the pelvis on POD 4, to look for evidence of VTE, if no other signs of VTE developed within this period. Although the postoperative protocol advised ultrasonography (US) or CT scan when a VTE event was suspected, none of the patients had any signs or symptoms suggestive of VTE during the study period. Central vein (CV) catheter-related thrombus was included as a VTE in this study, because it is a possible cause of PE and warrants the same attention as leg thrombus. The rates of SSI, hepatic failure after hepatectomy, and pancreatic fistula after pancreaticoduodenectomy were evaluated as postoperative morbidities. We also noted the length of postoperative hospital stay for each patient. Pancreatic fistula and hepatic failure were classified

3 according to the definition of the International Study Group of Pancreatic Fistula (ISGPF) [9] and the definition of the International Study Group of Liver Surgery (ISGLS) [0], respectively. Statistical analysis Statistical analyses were performed with JMP Pro 9 software (SAS Institute Inc.). The data distribution was tested for normality by examining the mean and standard error. Continuous variables are reported as median values and 25 75th percentile interquartile ranges (IQR). Comparisons were performed using the Mann Whitney U tests for non-normally distributed continuous variables. Chi-square and Fisher s exact (in cases of low frequencies) tests were used for comparisons of categorical variables. The relative risk and 95 % confidence interval (CI) are also reported. Results Between January 2008 and December 20, 349 patients underwent major hepatobiliary pancreatic surgery, such as pancreaticoduodenectomy, hemihepatectomy or greater with caudate lobectomy, extrahepatic bile duct resection, and hepatopancreaticoduodenectomy. Enoxaparin or fondaparinux were prescribed for postoperative chemical thromboprophylaxis in each period from January 2009 onward, as described in Materials and Methods. The chief surgeon for each case decided whether to give that patient chemical thromboprophylaxis, as well as the dose of fondaparinux when used, namely.5 or 2.5 mg/day. In this series, chemical thromboprophylaxis was administered to 207 patients (group T), as 4000 IU/day of enoxaparin in 66 patients (group E),.5 mg/day of fondaparinux in 48 patients (group F.5), and 2.5 mg/day of fondaparinux in 93 patients (group F2.5). The remaining 42 patients did not receive chemical thromboprophylaxis (group NT). All patients received mechanical VTE prevention with elastic stockings (ES) and intermittent pneumatic compression (IPC), with or without chemical thromboprophylaxis. Of the 349 patients enrolled in this study, 86 underwent, 27, 22, and 62 of whom were given 4000 IU/day of enoxaparin,.5 mg/day of fondaparinux, and 2.5 mg/day of fondaparinux, respectively. The remaining 66 patients received no chemical thrombophylaxis after (E 37, F.5 2, F2.5 62, NT 66). Similarly, 38 patients underwent (E 27, F.5 22, F2.5 23, NT 66) and 25 patients underwent (E 2, F.5 5, F2.5 8, NT 0). There were no differences in the proportion of operative methods, gender, or malignant diseases between groups T and NT. The operation time for group T was significantly longer than that for group NT; however, other factors such as intra-operative blood loss volume, intra-operative red cell concentrate (RCC) transfusion volume, and intra-operative fresh frozen plasma (FFP) volume, were similar between these groups. Significant differences were observed in the ratios of operative method, age, and the volume of intraoperative RCC transfusion among groups E, F.5, and F2.5 (Table ). Although the rate of postoperative hemorrhage was significantly higher in group T than in group NT [26.6 vs. 8.5 %; relative risk (RR) 3.4, 95 % CI ], especially for minor hemorrhage such as subcutaneous and intraabdominal hemorrhage (2.7 vs. 3.5 %; RR 6.7, 95 % CI ), the rate of major hemorrhage requiring blood transfusion and/or hemostasis with IVR or surgical intervention, in group T was equal to that in group NT (4.8 vs. 4.9 %; RR 0.98, 95 % CI ). With respect to the drugs administered, the rates of postoperative hemorrhage in group E (2.2 %, RR 2.5, 95 % CI ) and group F2.5 (37.6 %, RR 4.45, 95 % CI ) were significantly higher than that in group NT. There was also a significant increase in the risk of minor hemorrhage in group E and group F2.5 vs. group NT; however, the risk of major hemorrhage was not significantly different. The rate of postoperative hemorrhage in group F.5 was not significantly higher (2.5 %, RR.48, 95 % CI ) than that in group NT (Table 2). No epidural catheterrelated hemorrhage was observed in this series. The operative procedure did not affect these trends. Chemical thromboprophylaxis significantly increased the rate of postoperative hemorrhage, especially minor hemorrhage, but not the risk of major bleeding in the patients who underwent and. No significant differences were observed between groups T and NT among the patients that underwent (Table 3). Furthermore, chemical thromboprophylaxis did not increase the rate of SSI (Table 4). The incidence of postoperative VTE was significantly lower in group T than in group NT (2.9 vs. 7.7 %; RR 0.37, 95 % CI ). In most cases of postoperative VTE in our study, the affected veins included those involved in central venous catheterization and those related to an operative procedure, such as the portal and hepatic veins. Asymptomatic PE was detected in only one patient, who did not receive postoperative chemical thromboprophylaxis. There was no case of symptomatic PE (Table 5). Postoperative chemical thromboprophylaxis did not increase the rate of morbidity, defined as grade 3 or higher in the Clavien Dindo classification [] and it did not extend the postoperative hospital stay (Table 6). Thromboprophylaxis therapy did not increase significantly the incidence of pancreatic fistula (ISGPF grade B, C) after or liver failure (ISGLS grade C) after (Table 7).

4 Table Surgical treatments and intra-operative transfusions in patients undergoing major hepatobiliary pancreatic surgery stratified by postoperative pharmacologic thromboprophylaxis * p \ 0.05 compared with group NT ** p \ 0.05 among groups E, F.5, and F2.5 NT T p E F.5 F2.5 Procedure** 66 (46.5 %) 20 (58 %) (56. %) 2 (43.8 %) 62 (66.7 %) 66 (46.5 %) 72 (34.8 %) 27 (40.9 %) 22 (45.8 %) 23 (24.7 %) 0 (7.0 %) 5 (7.2 %) 2 (3 %) 5 (0.4 %) 8 (8.6 %) Gender F 55 (38.7 %) 78 (37.9 %) (28.8 %) 24 (5. %) 35 (37.6 %) M 87 (6.3 %) 28 (62. %) 47 (7.2 %) 23 (48.9 %) 58 (62.4 %) Disease Malignant 3 (79.6 %) 68 (8.2 %) (80.3 %) 35 (72.9 %) 80 (86 %) Benign 29 (20.4 %) 39 (8.8 %) 3 (9.7 %) 3 (27. %) 3 (4 %) Age** Median th IQR Ope time (min) Median \0.000* th IQR Blood loss (ml) Median th IQR RCC (unit)** Median th IQR FFP (unit) Median th IQR Discussion Several clinical guidelines in Japan [, 2] and Western countries [2 5] recommend chemical thromboprophylaxis after abdominal surgery. The latest antithrombotic guidelines (9th edition), from the American College of Chest Physicians (ACCP) [2], recommend the administration of low-molecular-weight heparin (LMWH) (grade B) or low-dose unfractionated heparin (LDUH) (grade B) for general and abdominal pelvic surgery in patients at high risk for VTE (Caprini score C5) but not for major bleeding complications. They also suggest adding mechanical prophylaxis with elastic stockings or IPC to the pharmacological thromboprophylaxis (grade 2C). According to these guidelines, fondaparinux, an indirect inhibitor of activated factor Xa, is equivalent to low-dose aspirin (grade 2C) or mechanical prophylaxis, preferably along with IPC (grade 2C) for general and abdominal pelvic surgery in patients at high risk for VTE, but only when both LMWH and unfractionated heparin are contraindicated or unavailable and the patients are not at high risk for major bleeding complications. While these recent guidelines recommend fondaparinux after LMWH and LDUH, it was recommended on an equal basis with

5 Table 2 Incidence and site of postoperative hemorrhage with vs.without chemical thromboprophylaxis against venous thromboembolism NT T RR 95 % CI E RR 95 % CI F.5 RR 95 % CI F2.5 RR 95 % CI Postoperative hemorrhage (8.5 %) - 30 (9.5 %) Postoperative hemorrhage? 7 (4.9 %) - 35 (95. %) Site Intraabdominal 5 (3.5 %) GI tract 2 (.4 %) Postoperative hemorrhage? 5 (3.5 %) - 37 (96.5 %) Site Subcutaneous 5 (3.5 %) Intraabdominal 3 (2. %) GI tract (0.7 %) Nasal 0 Retroperitoneal 0 55 (26.6 %) 52 (73.4 %) 0 (4.8 %) 97 (95.2 %) 0 (4.8 %) 0 45 (2.7 %) 62 (78.3 %) 30 (4.5 %) 2 (0. %) 2 ( %) (0.5 %) (0.5 %) (2.2 %) 52 (78.8 %) (.5 %) 65 (98.5 %) (.5 %) (9.7 %) 53 (80.3 %) (3.6 %) (9. %) (.5 %) (2.5 %) 42 (87.5 %) (6.3 %) 45 (93.8 %) (6.3 %) (6.3 %) 45 (93.8 %) (6.3 %) (2. %) (2. %) * (37.6 %) 58 (62.4 %) (6.5 %) 87 (93.5 %) (6.5 %) * (3.2 %) 64 (68.8 %) * (9.4 %) * (5. %) (. %) (. %) * p \ 0.05 compared with group NT

6 Table 3 Incidence of postoperative hemorrhage after different operative procedures with vs. without chemical thromboprophylaxis against venous thromboembolis NT T RR 95 % CI Postoperative hemorrhage Operative procedure? 4 (6. %) 35 (29.2 %) - 62 (93.9 %)? 6 (9. %) - 60 (90.9 %) (20.0 %) - 8 (80.0 %) Major hemorrhage Operative procedure (3.0 %)? 3 (9. %) (20.0 %) - 8 (80.0 %) Minor hemorrhage Operative procedure (3.0 %) - 64 (97.0 %)? 3 (9. %) - 63 (90.9 %)? 0 (0.0 %) - 0 (00.0 %) 85 (70.8 %) 8 (25.0 %) 54 (75.0 %) 2 (3.3 %) 3 (86.7 %) 5 (4.2 %) 4 (5.6 %) (6.7 %) 4 (93.3 %) 30 (25.0 %) 90 (75.0 %) 4 (9.4 %) 58 (80.6 %) (6.7 %) m (93.3 %) * p \ 0.05 compared with group NT * * * Table 4 Incidence of surgical site infection associated with prophylaxis against venous thromboembolism NT T RR 95 % CI Superficial incisional SSI 9 (20.4 %) - 3 (79.6 %) Deep incisional SSI? 8 (5.6 %) - 34 (94.4 %) Organ/space SSI? 45 (3.7 %) - 97 (68.3 %) Total? 59 (4.5 %) - 83 (58.5 %) 40 (9.3 %) 67 (80.7 %) 9 (4.3 %) 98 (95.7 %) 66 (3.9 %) 4 (68. %) 83 (40. %) 24 (59.9 %) p \ 0.05 compared with group NT LMWH and LDUH for cancer patients at a high risk for postoperative VTE in the previous ACCP guidelines (8th edition, 2008) [6] and other guidelines for postoperative VTE prevention by the National Comprehensive Cancer Network (NCCN) in 200 [4], the National Institute for Health and Clinical Excellence (NICE) in 200 [5], and the American Society of Clinical Oncology (ASCO) in 2007 [3]. Therefore, we used enoxaparin as well as fondaparinux for postoperative chemical thromboprophylaxis in the present study. While there is some evidence of the efficacy and safety of postoperative chemical thromboprophylaxis in American and European patients after abdominal surgery [7 22], few reports have demonstrated the benefits of chemical thromboprophylaxis after abdominal surgery in Japanese patients [23 25]. Moreover, to our knowledge, no report has validated the safety and efficacy of postoperative chemical thromboprophylaxis after hepatobiliary pancreatic surgery in Japanese or other Asian patients. It was reported that the incidence of PE after cancer surgery was significantly higher than that after surgery for noncancerous conditions (0.57 vs %) and that the incidence of PE after pancreatic surgery is very high (3.85 %) even in Japanese patients [26]. Hence, we conducted this study, which showed an increased risk of minor hemorrhage in

7 Table 5 Incidence of venous thromboembolism after prophylaxis VTE? (7.7 %) NT T RR 95 % CI 6 (2.9 %) - 3 (92.3 %) 20 (97. %) Details (VTE site) Hepatic vein 2 0 Portal vein 3 3 Inferior vena cava 0 Pulmonary artery 0 Associated with CV catheter 5 2 * p \ 0.05 compared with group NT * Table 6 Postoperative complication grade and hospital stay Complication grade NT T p (69.8 %) (27 %) 5 2 (3.2 %) (66.2 %) (30.8 %) 5 2 (3. %) (63.6 %) (8.2 %) 5 2 (8.2 %) Total (67.6 %) 7 (59.2 %) 46 (38.3 %) 3 (2.5 %) 44 (6. %) 27 (37.5 %) (.4 %) 3 (86.7 %) 2 (3.3 %) 0 28 (6.2 %) (28. %) 75 (35.9 %) 5 6 (4.3 %) 6 (2.9 %) Postoperative hospital stay (days) Median th IQR 8 20 Table 7 Incidence of pancreatic fistula and liver failure NT T RR 95 % CI Pancreatic fistula (ISGPF grade B, C)? 0 (5.2 %) 34 (28.3 %) - 56 (84.8 %) 86 (7.7 %) Liver failure (ISGLS grade C) (3.0 %) 6 (8.3 %) - 64 (97.0 %) 66 (9.7 %) Pancreatic fistula (ISGPF grade B, C)? 6 (60.0 %) 8 (53.3 %) - 4 (40.0 %) 7 (46.7 %) Liver failure (ISGLS grade C)? (0.0 %) (6.7 %) - 9 (90.0 %) p \ 0.05 vs. group NT 4 (93.3 %) patients receiving postoperative chemical thromboprophylaxis, but the incidence of postoperative major hemorrhage requiring blood transfusion or hemostatic intervention in these patients was equivalent to that in patients not receiving this therapy. Thus, chemical thromboprophylaxis seemed to increase only the risk of minor bleeding, requiring no treatment other than discontinuation of the chemical thromboprophylaxis. Although the increased risk of postoperative minor hemorrhage could result in SSI arising from retained blood or abdominal hematoma, we observed no increase in the incidence of SSI with postoperative chemical thromboprophylaxis in this series. Furthermore, this therapy did not increase the rate of postoperative complications or worsen the complication grades. The incidence of postoperative pancreatic fistula following / and hepatic failure after / was similar in all the patients, irrespective of chemical thromboprophylaxis. There was also no difference in the length of the postoperative hospital stay among the patients, irrespective of chemical thromboprophylaxis. Most of the patients in the present series had an epidural catheter inserted, whether they received chemical prophylaxis or not. This was removed on POD 5 at 7:00, 0 h after and 2 h before enoxaparin administration or at 9:00, 2 h after

8 and 3 h before fondaparinux administration, in accordance with the manufacturer s instructions for each drug. There was no incidence of epidural catheter-related hemorrhage in this series, indicating that chemical prophylaxis via an epidural catheter is relatively safe and not necessarily contraindicated; however, a large-scale study is needed to prove its safe use in major hepatobiliary pancreatic surgery. Despite removing the CV catheter as early as possible after the operation, we sometimes found unexpected venous thrombus in the superior vena cava, related to the CV catheter, on routine CT scans taken on POD 4. In this study, CV catheter-related thrombus was included in VTE because, like thrombus in the leg, it may cause PE. An important finding of this study was the significantly lower rate of postoperative VTE in patients who received postoperative chemical thromboprophylaxis vs. that in those who did not (2.9 vs. 7.7 %; 95 % CI ). In this study, postoperative VTE was evaluated by CT scans of the neck to the pelvis taken on POD 4 if no other apparent signs of VTE were noted. We may have missed the presence of asymptomatic thrombi outside of the range of the routine CT scan; however, apart from one patient with asymptomatic PE, no critical VTE or PE events occurred in any of the patients in this series. Overall, the administration of 4000 IU/day of enoxaparin and 2.5 mg/day of fondaparinux significantly increased the rate of postoperative minor hemorrhage, although no increase was observed after the administration of.5 mg/day of fondaparinux. Moreover, no postoperative VTE developed in the patients who received.5 mg/day of fondaparinux. As even minor postoperative hemorrhage is not a negligible complication after major hepatobiliary pancreatic surgery and as the risk of postoperative hemorrhage increases with lower coagulating function and prolonged prothrombin time following major hepatectomy, we consider that low-dose chemical thromboprophylaxis may be more suitable for the prevention of postoperative hemorrhage and is probably adequate prophylaxis against VTE in Japanese patients. Enoxaparin and fondaparinux can thus be safely used for the prevention of postoperative VTE, even after major hepatobiliary pancreatic surgery in Japanese patients. Further studies are necessary to establish whether a lower dose of chemical thromboprophylaxis should be given after major hepatobiliary pancreatic surgery. Conflict of interest Hiroki Hayashi and the other co-authors have no conflicts of interest. References. 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