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Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review
Pancreatology xxx (2017) 1e7
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Original Article
Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review Daisuke Hashimoto, MD, PhD, Shigeki Nakagawa, MD, PhD, Naoki Umezaki, MD, Takanobu Yamao, MD, Yuki Kitano, MD, Kensuke Yamamura, MD, Takayoshi Kaida, MD, Kota Arima, MD, Katsunori Imai, MD, PhD, Yo-ichi Yamashita, MD, PhD, Akira Chikamoto, MD, Hideo Baba, MD, PhD * Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 December 2016 Received in revised form 26 March 2017 Accepted 28 March 2017 Available online xxx
Background: /Objectives: Enoxaparin is low-molecular-weight heparin that is used for postoperative thromboprophylaxis. The purpose of this study was to evaluate the efficacy and safety of enoxaparin after pancreatic resection. We additionally carried out a literature review regarding venous thromboembolism (VTE) and postoperative bleeding mainly after hepatobiliary-pancreatic surgery. Methods: This was a prospective, single-arm study. Patients aged 20e79 years who planned to undergo pancreatic resection followed by postoperative anticoagulation therapy with enoxaparin were enrolled from 2013 to 2016. The exclusion criteria were low renal function, active bleeding, clinical signs of VTE at screening, or evidence of thromboembolic disease before surgery. The primary endpoint was the incidence of postoperative VTE. The secondary endpoint was the incidence of postoperative complications. For the literature review, PubMed was searched for relevant articles and the PRISMA guidelines were used. Results: In total, 103 patients were analyzed. Two patients (1.9%) developed asymptomatic VTE, and no patients developed symptomatic VTE. No in-hospital mortality occurred. Morbidities (ClavieneDindo grade IIIa) occurred in 29 patients (28.1%). Three patients (2.9%) developed intra-abdominal hemorrhage due to pseudoaneurysm formation after pancreaticoduodenectomy or distal pancreatectomy. The literature review included nine articles, and all indicated that the results of this study were feasible. Conclusion: This is the first prospective trial to focus on pharmacologic prophylaxis with enoxaparin after pancreatic surgery. Postoperative anticoagulant therapy with enoxaparin was used in patients who underwent pancreatic surgery with a low incidence of VTE and no increase in postoperative bleeding events compared with existing evidence. © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Keywords: Enoxaparin Pancreatic resection Venous thromboembolism
1. Introduction Venous thromboembolism (VTE), such as pulmonary embolism (PE) or deep venous thrombosis (DVT), is a major cause of morbidity and mortality in patients undergoing gastrointestinal surgery for malignancy [1e3]. Pharmacologic prophylaxis is
* Corresponding author. Department of Gastroenterological Surgery Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto-city 8608556, Japan. E-mail address: [email protected] (H. Baba).
therefore an important and recommended aspect of postoperative care [4e6]. Previous studies of VTE prophylaxis using low-molecularweight heparin (LMWH) such as enoxaparin in general surgery have indicated that LMWH is significantly associated with a lower incidence of VTE than is elastic compression without an increase in the incidence of severe adverse events and has efficacy and safety similar to those of unfractionated heparin [7]. Two Japanese randomized controlled trials (RCTs) indicated that enoxaparin (20 mg twice daily) is safe and effective for prevention of VTE in patients undergoing knee replacement [8] and surgical treatment of
http://dx.doi.org/10.1016/j.pan.2017.03.010 1424-3903/© 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
abdominal or pelvic cancer [9]. The incidence of VTE in patients with hepatobiliary-pancreatic (HBP) malignancy is relatively high [3,10]. Severe bleeding is a major adverse event that may occur during pharmacologic prophylaxis [3]. Thromboprophylaxis after major HBP surgery such as pancreaticoduodenectomy (PD) or hemihepatectomy is not yet routinely performed, especially in Japan, because these operations have a high risk of operative and postoperative bleeding [8,9,11,12]. The incidence of VTE in patients who have undergone pancreatic surgery is considered highest in those with HBP malignancies [1,12,13]C:\GetARef\Refs\enoxaparin.ref #25;. In addition, postoperative bleeding complications are still an important cause of postoperative mortality in patients undergoing pancreatic surgery [11,14e16]. Several studies of postoperative thromboprophylaxis with enoxaparin in patients who underwent HBP surgery, especially major hepatectomy, have been performed [12,17]. Yamashita et al. showed that postoperative anticoagulant therapy with enoxaparin could prevent portal vein thrombosis in patients who underwent hepatic resection for liver cancers [17]. Hayashi et al. indicated that chemical thromboprophylaxis is beneficial and can be safely used even after major HBP surgery [12]. Their study included 39 patients who underwent PD followed by enoxaparin treatment; however, their study was also retrospective. A prospective RCT about chemical thromboprophylaxis with enoxaparin included only one pancreatic surgery patient [9]. Reinke at al. indicated that the incidence of VTE decreased by preoperative thromboprophylaxis with unfractionated heparin, but not enoxaparin, in their retrospective study of 73 patients who underwent pancreatic surgery [13]. Thus, there is little evidence of the benefit and safety of enoxaparin after pancreatic surgery. Importantly, no prospective study has focused on the impact of enoxaparin after pancreatectomy. This prospective, single-arm clinical study was performed to investigate the efficacy and safety of postoperative thromboprophylaxis with enoxaparin in patients undergoing pancreatic surgery. In addition, we carried out a systematic literature review regarding VTE and postoperative bleeding mainly after HBP surgery.
2. Material and methods 2.1. Study design Because the American Society of Clinical Oncology Clinical (ASCO) Practice Guideline recommends consideration of pharmacologic thromboprophylaxis with either unfractionated heparin or LMWH in all patients with malignant disease undergoing major surgical intervention [5,6], we considered that a randomized study of patients with or without pharmacologic thromboprophylaxis should be avoided from an ethical standpoint. Thus, we designed a single-arm trial in which all enrolled patients received treatment. This single-center, single-arm, prospective study was performed at the Department of Gastroenterological Surgery, Kumamoto University Hospital, Japan from November 2013 to September 2016. The study was approved by the Institutional Review Board of Kumamoto University Hospital (#726). All procedures in this study were performed in accordance with the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all patients before their participation in the study.
2.2. Patient selection Male or female patients were eligible for the study if they were aged 20e79 years and undergoing planned, curative pancreatic resection [PD, hepatopancreaticoduodenectomy (HPD), distal pancreatectomy (DP), total pancreatectomy (TP), partial pancreatectomy (PP), or middle pancreatectomy (MP)] for a biliarypancreatic tumor. Both open laparotomy and laparoscopic surgeries were included in this study. Patients were excluded from the study if they were aged 80 years, had a life expectancy of 3 months after surgery, had either a hypersensitivity to heparin or thrombocytopenia due to heparin, had low renal function (defined as a creatinine clearance rate of <30 ml/min), or showed active bleeding. Screening of VTE by enhanced computed tomography (CT) and color doppler ultrasonography (US) was performed for all patients before surgery. Patients who had clinical signs of VTE or evidence of thromboembolic
Fig. 1. Study timeline of scheduled observations, tests, evaluations, and interventions. CT ¼ computed tomography; IPC ¼ intermittent pneumatic compression; US ¼ ultrasonography.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
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Fig. 2. Patient flow diagram. VTE ¼ venous thromboembolism.
Table 1 Patient characteristics and operative findings. Analyzed patients (n ¼ 103) Male: Female, n: n Age, median (range), y Performance status, 0: 1: 2, n: n: n Body mass index, median (range) Past history of laparotomy, n (%) Preoperative bile duct drainage, n (%) Concurrent disease
Malignant disease, n (%) Pancreatic cancer, n (%) Bile duct cancer (including ampullary cancer), n (%) Others, n (%) Procedures
Diabetes mellitus, n (%) Ischemic heart disease, n (%) Respiratory disease, n (%)
PD, n (%) DP, n (%) TP, n (%) PP, n (%) HPD, n (%) MP, n (%)
SMV-PV resection & reconstruction, n (%) Open surgery: Laparoscopic surgery, n: n
60: 43 66 (20e79) 85: 18: 0 22.7 (16.4e35.8) 20 (19.4%) 27 (26.2%) 30 (29.1%) 7 (6.8%) 6 (5.8%) 89 (86.4%) 60 (58.3%) 21 (20.4%) 8 (7.8%) 51 (49.5%) 33 (32.0%) 10 (9.7%) 5 (4.9%) 2 (1.9%) 2 (1.9%) 14 (13.6%) 88: 15
DP ¼ distal pancreatectomy; HPD ¼ hepatopancreaticoduodenectomy; MP ¼ middle pancreatectomy; PD ¼ pancreaticoduodenectomy; PP ¼ partial pancreatectomy; PV ¼ portal vein; SMV ¼ superior mesenteric vein; TP ¼ total pancreatectomy.
disease at this screening were excluded. Patients who required postoperative anticoagulant therapy with unfractionated heparin were excluded. Female patients with childbearing potential were also excluded from this study. Patients with a high risk of postoperative bleeding were excluded at the discretion of the attending surgeon.
2.3. Interventions The patients received a subcutaneous injection of enoxaparin (2000 IU) twice daily (Fig. 1). Enoxaparin was started 24e36 h after surgery and continued for 14 days or until hospital discharge. Intermittent pneumatic compression of the lower limbs was
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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D. Hashimoto et al. / Pancreatology xxx (2017) 1e7 Table 2 Postoperative outcomes. Analyzed patients (n ¼ 103) Operative time, minutes (range) Operative bleeding, ml (range) Blood transfusion, n (%) Complication (CD IIIa), n (%) POPF B grade B or C, n (%) In-hospital mortality, n (%) Postoperative hospital stay, median (range), day Symptomatic VTE (CD IV), n (%) Asymptomatic VTE (CD IIIa), n (%) During treatment period, n (%) During follow up period, n (%) Major bleeding (CD IIIa), n (%) During treatment period, n (%)
424 (107e864) 521 (0e3378) 16 (15.5%) 29 (28.1%) 11 (10.7%) 0 (0%) 22 (7e49) 0 (0%) 2 (1.9%) 1 (1.0%), PE þ DVT 1 (1.0%), PE þ DVT 3 (2.9%) 1 (1.0%), Pseudoaneurysm after PD 1 (1.0%), Pseudoaneurysm after DP 1 (1.0%), Pseudoaneurysm after PD 2 (1.9%) 1 (1.0%), Drain hole bleeding after PD 1 (1.0%), Drain hole bleeding after DP
During follow up period, n (%) Minor bleeding (CD I), n (%) During treatment period, n (%)
CD ¼ Clavien-Dindo; DP ¼ distal pancreatectomy; DVT ¼ deep venous thrombosis; PD ¼ pancreaticoduodenectomy; PE ¼ pulmonary embolism; POPF ¼ postoperative pancreatic fistula; VTE ¼ venous thromboembolism.
started in the operating room and continued for at least 3 days. The epidural catheter was usually removed on the second or third postoperative day, and enoxaparin was skipped on the morning of the day of surgery. For patients with relatively low renal function (defined as a creatinine clearance rate of 30e50 ml/min), 2000 IU of enoxaparin was administered once daily. Surgery and perioperative management were performed as previously described [18e20]. D2 lymph node dissection was performed in patients with malignant disease [21,22].
2.4. Assessments and outcome definitions The primary endpoint was the incidence of postoperative VTE (DVT or PE). VTE was identified by enhanced CT, which was routinely performed on postoperative day 6 ± 1, or by color Doppler ultrasonography performed within 1 day after the final administration of treatment. Additional enhanced CT was permitted when necessary. The secondary endpoint was the incidence of all postoperative adverse events. Postoperative complications were defined according to the ClavieneDindo scale [23]. Postoperative pancreatic fistula (POPF) was assessed as defined by the International Study Group for Pancreatic Surgery [24]. All patients were followed up for at least 28 days after surgery or until discharge.
2.6. Systematic literature review A literature review was planned and performed using methods specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses however a meta-analysis was not performed [25]. PubMed was searched for recent studies that reported postoperative VTE and thromboprophylaxis, especially with enoxaparin, and postoperative bleeding mainly after HBP surgery. Only English-language publications published from 2006 were selected. The selection process ensured that all articles included in the analysis were from peer-reviewed journals. All study designs were considered, although reviews, editorials, letters to the editor, case reports, and opinion pieces were excluded. Titles and abstracts of retrieved references were screened for relevance by two independent reviewers (N.S. and U.N.). In case of disagreements, a third reviewer (I.K.) cast the deciding vote. In the same fashion, the full texts of the potential studies were further analyzed by two independent reviewers (N.S. and U.N.) to determine whether they fully met the inclusion criteria. Disagreements at this stage were resolved by consensus and in consultation with a third reviewer (I.K.). The reviewers (N.S. and U.N.) extracted the data from the included articles.
3. Results 3.1. Patient disposition and analysis populations
2.5. Statistical analysis In the Japanese RCT [9], enoxaparin was used for 83 patients. The retrospective study by Hayashi et al. included 39 patients who underwent PD followed by enoxaparin treatment [12]. Reinke et al. focused on thromboprophylaxis with unfractionated heparin after pancreatic surgery and investigated 73 patients in their retrospective study [13]. In the present study, we considered that enoxaparin should be used for more patients than were included in these previous studies to compare the incidence of postoperative VTE and complications. Thus, we determined that the sample size should be at least 100 patients who were actually treated with enoxaparin. Descriptive statistics are presented as median (range) or number (percentage), as appropriate.
During the study period, 152 patients were planned to undergo curative pancreatic resection for pancreaticobiliary tumors and screened for this study (Fig. 2). Of these patients, 41 were excluded because of the need for postoperative anticoagulant therapy with unfractionated heparin (n ¼ 22), an age of 80 years (n ¼ 13), clinical signs of DVT or thromboembolic disease at screening (n ¼ 4), a creatinine clearance rate of <30 ml/min (n ¼ 1), or female sex with childbearing potential (n ¼ 1). Thus, 111 patients were enrolled in this study. However, three patients were excluded because their tumors were determined to be unresectable during laparotomy. In addition, one patient who underwent PD with combined resection of the portal vein for pancreatic head cancer was excluded. Collateral veins that readily bled had developed around the hepatoduodenal ligament, and the attending surgeon
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
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Fig. 3. Flow chart of literature search and extraction of studies meeting the inclusion criteria.
decided to exclude this patient because of the risk of postoperative bleeding. A total of 107 patients received enoxaparin treatment. Four were excluded because of inadequate VTE assessment (n ¼ 2) or poor compliance with treatment (n ¼ 2). Finally, 103 patients were analyzed.
3.2. Demographics and baseline medical characteristics The demographics and clinical characteristics of the analyzed patients are shown in Table 1. More than half (58.3%) of the patients were men. Their median age was 66 years (range, 20e79 years), and their median body mass index was 22.7 kg/m2 (range, 16.4e35.8 kg/m2). Twenty patients (19.4%) had a history of laparotomy. Preoperative bile duct drainage was performed in 27 patients (26.2%). With respect to concurrent disease, 30 patients (29.1%) had diabetes mellitus, 7 (6.8%) had ischemic heart disease, and 6 (5.8%) had respiratory disease. The target of pancreatic surgery was malignant disease such as pancreatic cancer in 89 patients (86.4%). The most common disease was pancreatic cancer (60 patients, 58.3%). The most common procedure was PD (51 patients, 49.5%) followed by DP (33 patients, 32.0%), TP (10 patients, 9.7%), PP (5 patients, 4.9%), HPD (2 patients, 1.9%), and MP (2 patients, 1.9%). Superior mesenteric vein/portal vein resection and reconstruction was performed in 14 patients (13.6%). Most patients (88, 85.4%) underwent open surgery, whereas laparoscopic surgery was performed in 15 patients (14.6%). Laparoscopic surgery included 14 cases of DP and 1 case of PP.
3.3. Operative outcomes and administration of enoxaparin The median operating time was 427 min (range, 107e864 min), and the median operative bleeding volume was 521 ml (range, 0e3378 ml). Intraoperative blood transfusion was administered to 16 patients (15.5%) (Table 2). The morbidity rate (ClavieneDindo IIIa) was 28.1% (29 patients) (Table 2). Grade B or C POPF developed in 11 patients (10.7%). No in-hospital mortality occurred. The median postoperative hospital stay was 22 days (range, 7e49 days). Administration of enoxaparin was initiated at a median time of 26.5 h (range, 24.0e33.5) after surgery. The median number of enoxaparin administrations was 27 (range, 17e27), and the median extent of exposure was 14 days (range, 9e14 days).
3.4. Incidence of VTE The overall incidence of VTE was 1.9% (2 patients) (Table 2). No patients developed symptomatic VTE (ClavieneDindo grade IV). Two patients developed asymptomatic VTE (ClavieneDindo grade IIIa) after open surgery; one patient developed the VTE on postoperative day 12 (during the treatment period) and the other on postoperative day 25 (during the follow-up period). Grade B POPF developed in both patients, and enhanced CT reveled PE and DVT. The D-dimer concentrations of these patients were elevated at 5.3 and 4.7 mg/ml, respectively. These patients were treated with a temporary inferior vena cava filter and unfractionated heparin and had recovered by the time of discharge. No patients who underwent laparoscopic surgery developed VTE.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
Table 3 Literature regarding VTE and postoperative bleeding after abdominal, especially HBP surgery. Author/[ref]/ Study year design
Operative procedure (n)
Anticoagulant therapy (n)
Incidence of VTE, %
Incidence of postoperative bleeding, %
Sakon [9] 2010
RCT
Abdominal cancer resection (114 including 1 pancreas surgery)
Enoxaparin (83) Control (31)
Enoxaparin 1.2% Control 19.4%
Zaghiyan [27] 2016
RCT
Maj. colorectal surgery (376)
Pre-ope. UFH (184) Post-ope. UFH (192)
Pre-ope. UFH 1.6% Post-ope. UFH 3.6%
Hayashi [12] 2014
Retrospective
Maj. HBP surgery (349 including 186 PD and 25 HPD)
CTP 2.9% Control 7.7%
Reinke [13] 2012 Yamashita [17] 2014
Retrospective Retrospective
Pancreatectomy (73)
CTP (enoxaparin 66 or fondaparinux, 141) Control (142) Pre-ope. UFH (39) Control (34) Enoxaparin (53) Control (228)
Enoxaparin: Maj. 4.6%, Min. 4.6% Control: Maj. 2.6%, Min. 5.3% Clinically significant bleeding Pre-ope. UFH 10.9% (any) Post-ope. UFH 12.5% (any) CTP: Maj. 4.8%, Min. 3.5% Control: Maj. 4.9%, Min. 21.7%
Yamashita [11] 2007 Rajarathinam [28] 2008 Kasumova [14] 2016 Asari [15] 2016 This study
Retrospective Retrospective Retrospective Retrospective Prospective
Maj. HBP surgery (69)
N.A
Pre-ope. UFH 2.6% Control 17.6% Enoxaparin (symptomatic) 0% Control (symptomatic) 0.4% N.A
Maj. 5.8%
PD (458)
N.A
N.A
Maj. 3.1%
PD (2548)
N.A
N.A
Maj. 5.5%, Min. 3.1%
Pancreatic resection (553)
N.A
N.A
Maj. 6.0%
Pancreatic resection (103)
Enoxaparin (103)
1.9%
Major 2.9%, Minor 1.9%
Hepatectomy (281)
Pre-ope. UFH: Maj. 5.1% Control: Maj. 0% Enoxaparin 1.9% (any) Control 0.4% (any)
CTP, chemical thromboprophylaxis; HBP, hepatobiliary-pancreatic; HPD, hepatopancreaticoduodenectomy; Maj, major; Min, minor; PD, pancreaticoduodenectomy; RCT, randomized control trial; UFH, unfractionated heparin; VTE, thromboembolism.
3.5. Incidence of postoperative hemorrhage The overall incidence of postoperative bleeding events was 4.9% (5 patients) (Table 2). Major bleeding (ClavieneDindo grade IIIa) developed in three patients (2.9%), and all cases of bleeding originated from rupture of a pseudoaneurysm after PD in two patients and after DP in one patient. All patients were treated with interventional radiology (transcatheter arterial embolization) and recovered. Because all pseudoaneurysms developed in patients with a POPF, we considered these pseudoaneurysms unlikely to be related to the study drug. Two of the three cases of major bleeding occurred during the treatment period, and the other case occurred during the follow-up period. Minor bleeding (ClavieneDindo grade I) developed in two patients (1.9%) during the treatment period. Both cases of bleeding originated from the drain hole after PD in one patient and after DP in the other. Both patients recovered immediately after discontinuation of enoxaparin. We considered these complications likely related to the study drug. 4. Discussion and literature review Pancreatic surgery is known to be a significant risk factor for VTE [12,26]. The ASCO Practice Guideline recommends that patients undergoing major cancer surgery receive thromboprophylaxis and that it should be continued for at least 7e10 days [5,6]. In this study, enoxaparin was continued for 14 days or until hospital discharge in accordance with a previous RCT [9]. The efficacy and safety of longer thromboprophylaxis, especially exceeding the in-hospital stay, should be analyzed in future studies because this issue remains a matter of debate in the current guidelines [4,5]. We carried out a systematic literature review to describe the efficacy of thromboprophylaxis, especially with enoxaparin, and the incidence of VTE and postoperative bleeding after abdominal surgery, especially in patients undergoing HBP surgery. Fig. 3 shows a flow chart of the descriptive analysis. In total, nine articles were
included in the analysis (Table 3). Thromboprophylaxis after major HBP surgery has not been routinely performed in Japan because of the high risk of operative and postoperative bleeding [8,9,11,12] (Table 3). Only a few retrospective studies have focused on postoperative thromboprophylaxis after major HBP surgery [12,13,17] (Table 3). Furthermore, no prospective studies have focused on thromboprophylaxis after pancreatic resection. Therefore, we conducted the present first prospective clinical trial to evaluate the efficacy and safety of postoperative thromboprophylaxis with enoxaparin in patients undergoing pancreatic surgery. The incidence of postoperative VTE, as the primary endpoint of this study, was compared with the existing evidence. No patients developed severe symptomatic VTE, and only two patients (1.9%) developed asymptomatic VTE. This high treatment efficacy is comparable with that in a previous prospective randomized trial of postoperative pharmacologic thromboprophylaxis with enoxaparin after curative abdominal or pelvic cancer surgery [9], and in another trial of perioperative unfractionated heparin for colorectal surgery [27] (Table 3). In the former study, the incidence of VTE in the patients treated with enoxaparin was 1.2% [9]. In the latter study, the incidence of VTE was 1.6%e3.6% [27]. The secondary endpoint of the present study was the incidence of all postoperative adverse events. Eleven patients (10.7%) developed a grade B or C POPF; however, no in-hospital mortality occurred. Moreover, the incidence of postoperative hemorrhage (4.9%) in this study was comparable with not only a previous prospective trial of enoxaparin after surgical treatment of abdominal or pelvic cancer (9.2%) [9], but also previous retrospective studies of postpancreatectomy hemorrhage (about 6%e8%) [11,14e16,28] (Table 3). The cases of major bleeding in the present study were associated with POPF, and the affected patients immediately recovered after intervention. These results may indicate that administration of enoxaparin after pancreatic surgery does not increase the risk of postoperative bleeding. There were some limitations in this study. First, this was a
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
single-arm trial and the sample size may be small to draw the conclusion in this study, because incidence of DVT as primary endpoint and post-operative hemorrhage as secondary endpoint were less than 5%. Further randomized studies including at least 200e300 patients should be designed to compare enoxaparin with other types of pharmacologic thromboprophylaxis to evaluate less incidence of endpoints. Second, our study included 15 patients (14.6%) who underwent laparoscopic surgery, and none developed VTE. Although a previous meta-analysis indicated that the incidence of postoperative VTE was not significantly different between laparoscopic versus open surgery for colorectal disease [29], this topic has not been adequately discussed in pancreatic surgery and should be analyzed in the future. Third, our study did not routinely evaluate the D-dimer concentration. Some studies have shown that D-dimer measurement is effective for screening of DVT [30,31]. However, other studies have indicated that the benefit of D-dimer testing is limited to ruling out VTE [32]. The efficacy of preoperative D-dimer testing should be analyzed and discussed in the future. Fourth, we performed enhanced CT on postoperative day 6 ± 1 and color Doppler ultrasonography 1 day after the final administration of treatment to identify VTE. The methods of identifying VTE differ among studies [9,27]. The efficacy of each method used to evaluate postoperative VTE should be compared in a future study. In conclusion, this is the first prospective trial to focus on pharmacologic prophylaxis with enoxaparin after pancreatic surgery. The results of this single-center, single-arm prospective study indicate that enoxaparin may prevent VTE in the majority of patients undergoing pancreatectomy without increasing the incidence of adverse events, such as postoperative bleeding, compared with existing evidence. These findings should be confirmed in further studies including more patients.
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Acknowledgments
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The authors have no conflicts of interest to declare. No funding was received for this study.
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Japanese patients undergoing curative abdominal or pelvic cancer surgery: results from a multicenter, randomized, open-label study. Thromb Res 2010;125:e65e70. Tzeng C, Curley S, Vauthey J, Aloia T. Distinct predictors of pre- versus postdischarge venous thromboembolism after hepatectomy: analysis of 7621 NSQIP patients. HPB Oxf 2013;15:773e80. Yamashita Y, Taketomi A, Fukuzawa K, Tsujita E, Harimoto N, Kitagawa D, et al. Risk factors for and management of delayed intraperitoneal hemorrhage after pancreatic and biliary surgery. Am J Surg 2007;193:454e9. Hayashi H, Morikawa T, Yoshida H, Motoi F, Okada T, Nakagawa K, et al. Safety of postoperative thromboprophylaxis after major hepatobiliary-pancreatic surgery in Japanese patients. Surg Today 2014;44:1660e8. Reinke C, Drebin J, Kreider S, Kean C, Resnick A, Raper S, et al. Timing of preoperative pharmacoprophylaxis for pancreatic surgery patients: a venous thromboembolism reduction initiative. Ann Surg Oncol 2012;19:19e25. Kasumova G, Eskander M, Kent T, Ng S, Moser A, Ahmed M, et al. Hemorrhage after pancreaticoduodenectomy: does timing matter? HPB Oxf 2016;18: 861e9. Asari S, Matsumoto I, Toyama H, Yamaguchi M, Okada T, Shinzeki M, et al. Recommendation of treatment strategy for postpancreatectomy hemorrhage: lessons from a single-center experience in 35 patients. Pancreatology 2016;16:454e63. Hasegawa T, Ota H, Matsuura T, Seiji K, Mugikura S, Motoi F, et al. Endovascular treatment of hepatic artery pseudoaneurysm after pancreaticoduodenectomy: risk factors associated with mortality and complications. J Vasc Interv Radiol 2016;S1051e0443:30037e9. Yamashita Y, Bekki Y, Imai D, Ikegami T, Yoshizumi T, Ikeda T, et al. Efficacy of postoperative anticoagulation therapy with enoxaparin for portal vein thrombosis after hepatic resection in patients with liver cancer. Thromb. Res 2014;134(Supplement):826e31. Hashimoto D, Chikamoto A, Arima K, Taki K, Inoue R, Imai K, et al. Unused sterile instruments for closure prevent wound surgical site infection after pancreatic surgery. J Surg Res 2016;205:38e42. Hashimoto D, Chikamoto A, Harimoto N, Ikegami T, Uchiyama H, Yoshizumi T, et al. A comparative study on the complications of conventional and end-toside inserting pancreatojejunostomy after pancreaticoduodenectomy. Surg Today 2017;47:238e44. Hashimoto D, Chikamoto A, Taki K, Arima K, Yamashita Y, Ohmuraya M, et al. Residual total pancreatectomy: short- and long-term outcomes. Pancreatology 2016;16:646e51. Japan Pancreas Society. General rules for the study of pancreatic cancer. the sixth ed. July 2009. Japanese society of hepato-biliary-pancreatic surgery. General rules for surgical and pathological studies on cancer of the biliary tract. the sixth ed. September 2013. DeOliveira ML, Winter JM, Schafer M, Cunningham SC, Cameron JL, Yeo CJ, et al. Assessment of complications after pancreatic surgery: a novel grading system applied to 633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;244:931e7. discussion 9. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005;138:8e13. Liberati A, Altman D, Tetzlaff J, Mulrow C, Gøtzsche P, Ioannidis J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:w65e94. Munoz Martin A, Garcia Alfonso P, Ruperez Blanco A, Perez Ramirez S, Blanco Codesido M, Martin Jimenez M. Incidence of venous thromboembolism (VTE) in ambulatory pancreatic cancer patients receiving chemotherapy and analysis of Khorana's predictive model. Clin Transl Oncol 2014;16:927e30. Zaghiyan K, Sax H, Miraflor E, Cossman D, Wagner W, Mirocha J, et al. Timing of chemical thromboprophylaxis and deep vein thrombosis in major colorectal surgery: a randomized clinical trial. Ann Surg 2016;264:632e9. Rajarathinam G, Kannan D, Vimalraj V, Amudhan A, Rajendran S, Jyotibasu D, et al. Post pancreaticoduodenectomy haemorrhage: outcome prediction based on new ISGPS Clinical severity grading. HPB Oxf 2008;10:363e70. Cui G, Wang X, Yao W, Li H. Incidence of postoperative venous thromboembolism after laparoscopic versus open colorectal cancer surgery: a metaanalysis. Surg Laparosc Endosc Percutan Tech 2013;23:128e34. de Moerloose P, Minazio P, Reber G, Perrier A, Bounameaux H. D-dimer determination to exclude pulmonary embolism: a two-step approach using latex assay as a screening tool. Thromb Haemost 1994;72:89e91. Matsuo H, Nakajima Y, Ogawa T, Mo M, Tazaki J, Doi T, et al. Evaluation of Ddimer in screening deep vein thrombosis in hospitalized Japanese patients with acute medical diseases/episodes. Ann Vasc Dis 2016;9:193e200. van Es N, van der Hulle T, Büller H, Klok F, Huisman M, Galipienzo J, et al. Stand-alone D-dimer testing to rule out acute pulmonary embolism. J Thromb Haemost 2017 Feb;15(2):323e8 [Epub ahead of print].
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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Original Article
Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review Daisuke Hashimoto, MD, PhD, Shigeki Nakagawa, MD, PhD, Naoki Umezaki, MD, Takanobu Yamao, MD, Yuki Kitano, MD, Kensuke Yamamura, MD, Takayoshi Kaida, MD, Kota Arima, MD, Katsunori Imai, MD, PhD, Yo-ichi Yamashita, MD, PhD, Akira Chikamoto, MD, Hideo Baba, MD, PhD * Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 December 2016 Received in revised form 26 March 2017 Accepted 28 March 2017 Available online xxx
Background: /Objectives: Enoxaparin is low-molecular-weight heparin that is used for postoperative thromboprophylaxis. The purpose of this study was to evaluate the efficacy and safety of enoxaparin after pancreatic resection. We additionally carried out a literature review regarding venous thromboembolism (VTE) and postoperative bleeding mainly after hepatobiliary-pancreatic surgery. Methods: This was a prospective, single-arm study. Patients aged 20e79 years who planned to undergo pancreatic resection followed by postoperative anticoagulation therapy with enoxaparin were enrolled from 2013 to 2016. The exclusion criteria were low renal function, active bleeding, clinical signs of VTE at screening, or evidence of thromboembolic disease before surgery. The primary endpoint was the incidence of postoperative VTE. The secondary endpoint was the incidence of postoperative complications. For the literature review, PubMed was searched for relevant articles and the PRISMA guidelines were used. Results: In total, 103 patients were analyzed. Two patients (1.9%) developed asymptomatic VTE, and no patients developed symptomatic VTE. No in-hospital mortality occurred. Morbidities (ClavieneDindo grade IIIa) occurred in 29 patients (28.1%). Three patients (2.9%) developed intra-abdominal hemorrhage due to pseudoaneurysm formation after pancreaticoduodenectomy or distal pancreatectomy. The literature review included nine articles, and all indicated that the results of this study were feasible. Conclusion: This is the first prospective trial to focus on pharmacologic prophylaxis with enoxaparin after pancreatic surgery. Postoperative anticoagulant therapy with enoxaparin was used in patients who underwent pancreatic surgery with a low incidence of VTE and no increase in postoperative bleeding events compared with existing evidence. © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Keywords: Enoxaparin Pancreatic resection Venous thromboembolism
1. Introduction Venous thromboembolism (VTE), such as pulmonary embolism (PE) or deep venous thrombosis (DVT), is a major cause of morbidity and mortality in patients undergoing gastrointestinal surgery for malignancy [1e3]. Pharmacologic prophylaxis is
* Corresponding author. Department of Gastroenterological Surgery Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto-city 8608556, Japan. E-mail address: [email protected] (H. Baba).
therefore an important and recommended aspect of postoperative care [4e6]. Previous studies of VTE prophylaxis using low-molecularweight heparin (LMWH) such as enoxaparin in general surgery have indicated that LMWH is significantly associated with a lower incidence of VTE than is elastic compression without an increase in the incidence of severe adverse events and has efficacy and safety similar to those of unfractionated heparin [7]. Two Japanese randomized controlled trials (RCTs) indicated that enoxaparin (20 mg twice daily) is safe and effective for prevention of VTE in patients undergoing knee replacement [8] and surgical treatment of
http://dx.doi.org/10.1016/j.pan.2017.03.010 1424-3903/© 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
abdominal or pelvic cancer [9]. The incidence of VTE in patients with hepatobiliary-pancreatic (HBP) malignancy is relatively high [3,10]. Severe bleeding is a major adverse event that may occur during pharmacologic prophylaxis [3]. Thromboprophylaxis after major HBP surgery such as pancreaticoduodenectomy (PD) or hemihepatectomy is not yet routinely performed, especially in Japan, because these operations have a high risk of operative and postoperative bleeding [8,9,11,12]. The incidence of VTE in patients who have undergone pancreatic surgery is considered highest in those with HBP malignancies [1,12,13]C:\GetARef\Refs\enoxaparin.ref #25;. In addition, postoperative bleeding complications are still an important cause of postoperative mortality in patients undergoing pancreatic surgery [11,14e16]. Several studies of postoperative thromboprophylaxis with enoxaparin in patients who underwent HBP surgery, especially major hepatectomy, have been performed [12,17]. Yamashita et al. showed that postoperative anticoagulant therapy with enoxaparin could prevent portal vein thrombosis in patients who underwent hepatic resection for liver cancers [17]. Hayashi et al. indicated that chemical thromboprophylaxis is beneficial and can be safely used even after major HBP surgery [12]. Their study included 39 patients who underwent PD followed by enoxaparin treatment; however, their study was also retrospective. A prospective RCT about chemical thromboprophylaxis with enoxaparin included only one pancreatic surgery patient [9]. Reinke at al. indicated that the incidence of VTE decreased by preoperative thromboprophylaxis with unfractionated heparin, but not enoxaparin, in their retrospective study of 73 patients who underwent pancreatic surgery [13]. Thus, there is little evidence of the benefit and safety of enoxaparin after pancreatic surgery. Importantly, no prospective study has focused on the impact of enoxaparin after pancreatectomy. This prospective, single-arm clinical study was performed to investigate the efficacy and safety of postoperative thromboprophylaxis with enoxaparin in patients undergoing pancreatic surgery. In addition, we carried out a systematic literature review regarding VTE and postoperative bleeding mainly after HBP surgery.
2. Material and methods 2.1. Study design Because the American Society of Clinical Oncology Clinical (ASCO) Practice Guideline recommends consideration of pharmacologic thromboprophylaxis with either unfractionated heparin or LMWH in all patients with malignant disease undergoing major surgical intervention [5,6], we considered that a randomized study of patients with or without pharmacologic thromboprophylaxis should be avoided from an ethical standpoint. Thus, we designed a single-arm trial in which all enrolled patients received treatment. This single-center, single-arm, prospective study was performed at the Department of Gastroenterological Surgery, Kumamoto University Hospital, Japan from November 2013 to September 2016. The study was approved by the Institutional Review Board of Kumamoto University Hospital (#726). All procedures in this study were performed in accordance with the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all patients before their participation in the study.
2.2. Patient selection Male or female patients were eligible for the study if they were aged 20e79 years and undergoing planned, curative pancreatic resection [PD, hepatopancreaticoduodenectomy (HPD), distal pancreatectomy (DP), total pancreatectomy (TP), partial pancreatectomy (PP), or middle pancreatectomy (MP)] for a biliarypancreatic tumor. Both open laparotomy and laparoscopic surgeries were included in this study. Patients were excluded from the study if they were aged 80 years, had a life expectancy of 3 months after surgery, had either a hypersensitivity to heparin or thrombocytopenia due to heparin, had low renal function (defined as a creatinine clearance rate of <30 ml/min), or showed active bleeding. Screening of VTE by enhanced computed tomography (CT) and color doppler ultrasonography (US) was performed for all patients before surgery. Patients who had clinical signs of VTE or evidence of thromboembolic
Fig. 1. Study timeline of scheduled observations, tests, evaluations, and interventions. CT ¼ computed tomography; IPC ¼ intermittent pneumatic compression; US ¼ ultrasonography.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
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Fig. 2. Patient flow diagram. VTE ¼ venous thromboembolism.
Table 1 Patient characteristics and operative findings. Analyzed patients (n ¼ 103) Male: Female, n: n Age, median (range), y Performance status, 0: 1: 2, n: n: n Body mass index, median (range) Past history of laparotomy, n (%) Preoperative bile duct drainage, n (%) Concurrent disease
Malignant disease, n (%) Pancreatic cancer, n (%) Bile duct cancer (including ampullary cancer), n (%) Others, n (%) Procedures
Diabetes mellitus, n (%) Ischemic heart disease, n (%) Respiratory disease, n (%)
PD, n (%) DP, n (%) TP, n (%) PP, n (%) HPD, n (%) MP, n (%)
SMV-PV resection & reconstruction, n (%) Open surgery: Laparoscopic surgery, n: n
60: 43 66 (20e79) 85: 18: 0 22.7 (16.4e35.8) 20 (19.4%) 27 (26.2%) 30 (29.1%) 7 (6.8%) 6 (5.8%) 89 (86.4%) 60 (58.3%) 21 (20.4%) 8 (7.8%) 51 (49.5%) 33 (32.0%) 10 (9.7%) 5 (4.9%) 2 (1.9%) 2 (1.9%) 14 (13.6%) 88: 15
DP ¼ distal pancreatectomy; HPD ¼ hepatopancreaticoduodenectomy; MP ¼ middle pancreatectomy; PD ¼ pancreaticoduodenectomy; PP ¼ partial pancreatectomy; PV ¼ portal vein; SMV ¼ superior mesenteric vein; TP ¼ total pancreatectomy.
disease at this screening were excluded. Patients who required postoperative anticoagulant therapy with unfractionated heparin were excluded. Female patients with childbearing potential were also excluded from this study. Patients with a high risk of postoperative bleeding were excluded at the discretion of the attending surgeon.
2.3. Interventions The patients received a subcutaneous injection of enoxaparin (2000 IU) twice daily (Fig. 1). Enoxaparin was started 24e36 h after surgery and continued for 14 days or until hospital discharge. Intermittent pneumatic compression of the lower limbs was
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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D. Hashimoto et al. / Pancreatology xxx (2017) 1e7 Table 2 Postoperative outcomes. Analyzed patients (n ¼ 103) Operative time, minutes (range) Operative bleeding, ml (range) Blood transfusion, n (%) Complication (CD IIIa), n (%) POPF B grade B or C, n (%) In-hospital mortality, n (%) Postoperative hospital stay, median (range), day Symptomatic VTE (CD IV), n (%) Asymptomatic VTE (CD IIIa), n (%) During treatment period, n (%) During follow up period, n (%) Major bleeding (CD IIIa), n (%) During treatment period, n (%)
424 (107e864) 521 (0e3378) 16 (15.5%) 29 (28.1%) 11 (10.7%) 0 (0%) 22 (7e49) 0 (0%) 2 (1.9%) 1 (1.0%), PE þ DVT 1 (1.0%), PE þ DVT 3 (2.9%) 1 (1.0%), Pseudoaneurysm after PD 1 (1.0%), Pseudoaneurysm after DP 1 (1.0%), Pseudoaneurysm after PD 2 (1.9%) 1 (1.0%), Drain hole bleeding after PD 1 (1.0%), Drain hole bleeding after DP
During follow up period, n (%) Minor bleeding (CD I), n (%) During treatment period, n (%)
CD ¼ Clavien-Dindo; DP ¼ distal pancreatectomy; DVT ¼ deep venous thrombosis; PD ¼ pancreaticoduodenectomy; PE ¼ pulmonary embolism; POPF ¼ postoperative pancreatic fistula; VTE ¼ venous thromboembolism.
started in the operating room and continued for at least 3 days. The epidural catheter was usually removed on the second or third postoperative day, and enoxaparin was skipped on the morning of the day of surgery. For patients with relatively low renal function (defined as a creatinine clearance rate of 30e50 ml/min), 2000 IU of enoxaparin was administered once daily. Surgery and perioperative management were performed as previously described [18e20]. D2 lymph node dissection was performed in patients with malignant disease [21,22].
2.4. Assessments and outcome definitions The primary endpoint was the incidence of postoperative VTE (DVT or PE). VTE was identified by enhanced CT, which was routinely performed on postoperative day 6 ± 1, or by color Doppler ultrasonography performed within 1 day after the final administration of treatment. Additional enhanced CT was permitted when necessary. The secondary endpoint was the incidence of all postoperative adverse events. Postoperative complications were defined according to the ClavieneDindo scale [23]. Postoperative pancreatic fistula (POPF) was assessed as defined by the International Study Group for Pancreatic Surgery [24]. All patients were followed up for at least 28 days after surgery or until discharge.
2.6. Systematic literature review A literature review was planned and performed using methods specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for reporting systematic reviews and meta-analyses however a meta-analysis was not performed [25]. PubMed was searched for recent studies that reported postoperative VTE and thromboprophylaxis, especially with enoxaparin, and postoperative bleeding mainly after HBP surgery. Only English-language publications published from 2006 were selected. The selection process ensured that all articles included in the analysis were from peer-reviewed journals. All study designs were considered, although reviews, editorials, letters to the editor, case reports, and opinion pieces were excluded. Titles and abstracts of retrieved references were screened for relevance by two independent reviewers (N.S. and U.N.). In case of disagreements, a third reviewer (I.K.) cast the deciding vote. In the same fashion, the full texts of the potential studies were further analyzed by two independent reviewers (N.S. and U.N.) to determine whether they fully met the inclusion criteria. Disagreements at this stage were resolved by consensus and in consultation with a third reviewer (I.K.). The reviewers (N.S. and U.N.) extracted the data from the included articles.
3. Results 3.1. Patient disposition and analysis populations
2.5. Statistical analysis In the Japanese RCT [9], enoxaparin was used for 83 patients. The retrospective study by Hayashi et al. included 39 patients who underwent PD followed by enoxaparin treatment [12]. Reinke et al. focused on thromboprophylaxis with unfractionated heparin after pancreatic surgery and investigated 73 patients in their retrospective study [13]. In the present study, we considered that enoxaparin should be used for more patients than were included in these previous studies to compare the incidence of postoperative VTE and complications. Thus, we determined that the sample size should be at least 100 patients who were actually treated with enoxaparin. Descriptive statistics are presented as median (range) or number (percentage), as appropriate.
During the study period, 152 patients were planned to undergo curative pancreatic resection for pancreaticobiliary tumors and screened for this study (Fig. 2). Of these patients, 41 were excluded because of the need for postoperative anticoagulant therapy with unfractionated heparin (n ¼ 22), an age of 80 years (n ¼ 13), clinical signs of DVT or thromboembolic disease at screening (n ¼ 4), a creatinine clearance rate of <30 ml/min (n ¼ 1), or female sex with childbearing potential (n ¼ 1). Thus, 111 patients were enrolled in this study. However, three patients were excluded because their tumors were determined to be unresectable during laparotomy. In addition, one patient who underwent PD with combined resection of the portal vein for pancreatic head cancer was excluded. Collateral veins that readily bled had developed around the hepatoduodenal ligament, and the attending surgeon
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
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Fig. 3. Flow chart of literature search and extraction of studies meeting the inclusion criteria.
decided to exclude this patient because of the risk of postoperative bleeding. A total of 107 patients received enoxaparin treatment. Four were excluded because of inadequate VTE assessment (n ¼ 2) or poor compliance with treatment (n ¼ 2). Finally, 103 patients were analyzed.
3.2. Demographics and baseline medical characteristics The demographics and clinical characteristics of the analyzed patients are shown in Table 1. More than half (58.3%) of the patients were men. Their median age was 66 years (range, 20e79 years), and their median body mass index was 22.7 kg/m2 (range, 16.4e35.8 kg/m2). Twenty patients (19.4%) had a history of laparotomy. Preoperative bile duct drainage was performed in 27 patients (26.2%). With respect to concurrent disease, 30 patients (29.1%) had diabetes mellitus, 7 (6.8%) had ischemic heart disease, and 6 (5.8%) had respiratory disease. The target of pancreatic surgery was malignant disease such as pancreatic cancer in 89 patients (86.4%). The most common disease was pancreatic cancer (60 patients, 58.3%). The most common procedure was PD (51 patients, 49.5%) followed by DP (33 patients, 32.0%), TP (10 patients, 9.7%), PP (5 patients, 4.9%), HPD (2 patients, 1.9%), and MP (2 patients, 1.9%). Superior mesenteric vein/portal vein resection and reconstruction was performed in 14 patients (13.6%). Most patients (88, 85.4%) underwent open surgery, whereas laparoscopic surgery was performed in 15 patients (14.6%). Laparoscopic surgery included 14 cases of DP and 1 case of PP.
3.3. Operative outcomes and administration of enoxaparin The median operating time was 427 min (range, 107e864 min), and the median operative bleeding volume was 521 ml (range, 0e3378 ml). Intraoperative blood transfusion was administered to 16 patients (15.5%) (Table 2). The morbidity rate (ClavieneDindo IIIa) was 28.1% (29 patients) (Table 2). Grade B or C POPF developed in 11 patients (10.7%). No in-hospital mortality occurred. The median postoperative hospital stay was 22 days (range, 7e49 days). Administration of enoxaparin was initiated at a median time of 26.5 h (range, 24.0e33.5) after surgery. The median number of enoxaparin administrations was 27 (range, 17e27), and the median extent of exposure was 14 days (range, 9e14 days).
3.4. Incidence of VTE The overall incidence of VTE was 1.9% (2 patients) (Table 2). No patients developed symptomatic VTE (ClavieneDindo grade IV). Two patients developed asymptomatic VTE (ClavieneDindo grade IIIa) after open surgery; one patient developed the VTE on postoperative day 12 (during the treatment period) and the other on postoperative day 25 (during the follow-up period). Grade B POPF developed in both patients, and enhanced CT reveled PE and DVT. The D-dimer concentrations of these patients were elevated at 5.3 and 4.7 mg/ml, respectively. These patients were treated with a temporary inferior vena cava filter and unfractionated heparin and had recovered by the time of discharge. No patients who underwent laparoscopic surgery developed VTE.
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
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Table 3 Literature regarding VTE and postoperative bleeding after abdominal, especially HBP surgery. Author/[ref]/ Study year design
Operative procedure (n)
Anticoagulant therapy (n)
Incidence of VTE, %
Incidence of postoperative bleeding, %
Sakon [9] 2010
RCT
Abdominal cancer resection (114 including 1 pancreas surgery)
Enoxaparin (83) Control (31)
Enoxaparin 1.2% Control 19.4%
Zaghiyan [27] 2016
RCT
Maj. colorectal surgery (376)
Pre-ope. UFH (184) Post-ope. UFH (192)
Pre-ope. UFH 1.6% Post-ope. UFH 3.6%
Hayashi [12] 2014
Retrospective
Maj. HBP surgery (349 including 186 PD and 25 HPD)
CTP 2.9% Control 7.7%
Reinke [13] 2012 Yamashita [17] 2014
Retrospective Retrospective
Pancreatectomy (73)
CTP (enoxaparin 66 or fondaparinux, 141) Control (142) Pre-ope. UFH (39) Control (34) Enoxaparin (53) Control (228)
Enoxaparin: Maj. 4.6%, Min. 4.6% Control: Maj. 2.6%, Min. 5.3% Clinically significant bleeding Pre-ope. UFH 10.9% (any) Post-ope. UFH 12.5% (any) CTP: Maj. 4.8%, Min. 3.5% Control: Maj. 4.9%, Min. 21.7%
Yamashita [11] 2007 Rajarathinam [28] 2008 Kasumova [14] 2016 Asari [15] 2016 This study
Retrospective Retrospective Retrospective Retrospective Prospective
Maj. HBP surgery (69)
N.A
Pre-ope. UFH 2.6% Control 17.6% Enoxaparin (symptomatic) 0% Control (symptomatic) 0.4% N.A
Maj. 5.8%
PD (458)
N.A
N.A
Maj. 3.1%
PD (2548)
N.A
N.A
Maj. 5.5%, Min. 3.1%
Pancreatic resection (553)
N.A
N.A
Maj. 6.0%
Pancreatic resection (103)
Enoxaparin (103)
1.9%
Major 2.9%, Minor 1.9%
Hepatectomy (281)
Pre-ope. UFH: Maj. 5.1% Control: Maj. 0% Enoxaparin 1.9% (any) Control 0.4% (any)
CTP, chemical thromboprophylaxis; HBP, hepatobiliary-pancreatic; HPD, hepatopancreaticoduodenectomy; Maj, major; Min, minor; PD, pancreaticoduodenectomy; RCT, randomized control trial; UFH, unfractionated heparin; VTE, thromboembolism.
3.5. Incidence of postoperative hemorrhage The overall incidence of postoperative bleeding events was 4.9% (5 patients) (Table 2). Major bleeding (ClavieneDindo grade IIIa) developed in three patients (2.9%), and all cases of bleeding originated from rupture of a pseudoaneurysm after PD in two patients and after DP in one patient. All patients were treated with interventional radiology (transcatheter arterial embolization) and recovered. Because all pseudoaneurysms developed in patients with a POPF, we considered these pseudoaneurysms unlikely to be related to the study drug. Two of the three cases of major bleeding occurred during the treatment period, and the other case occurred during the follow-up period. Minor bleeding (ClavieneDindo grade I) developed in two patients (1.9%) during the treatment period. Both cases of bleeding originated from the drain hole after PD in one patient and after DP in the other. Both patients recovered immediately after discontinuation of enoxaparin. We considered these complications likely related to the study drug. 4. Discussion and literature review Pancreatic surgery is known to be a significant risk factor for VTE [12,26]. The ASCO Practice Guideline recommends that patients undergoing major cancer surgery receive thromboprophylaxis and that it should be continued for at least 7e10 days [5,6]. In this study, enoxaparin was continued for 14 days or until hospital discharge in accordance with a previous RCT [9]. The efficacy and safety of longer thromboprophylaxis, especially exceeding the in-hospital stay, should be analyzed in future studies because this issue remains a matter of debate in the current guidelines [4,5]. We carried out a systematic literature review to describe the efficacy of thromboprophylaxis, especially with enoxaparin, and the incidence of VTE and postoperative bleeding after abdominal surgery, especially in patients undergoing HBP surgery. Fig. 3 shows a flow chart of the descriptive analysis. In total, nine articles were
included in the analysis (Table 3). Thromboprophylaxis after major HBP surgery has not been routinely performed in Japan because of the high risk of operative and postoperative bleeding [8,9,11,12] (Table 3). Only a few retrospective studies have focused on postoperative thromboprophylaxis after major HBP surgery [12,13,17] (Table 3). Furthermore, no prospective studies have focused on thromboprophylaxis after pancreatic resection. Therefore, we conducted the present first prospective clinical trial to evaluate the efficacy and safety of postoperative thromboprophylaxis with enoxaparin in patients undergoing pancreatic surgery. The incidence of postoperative VTE, as the primary endpoint of this study, was compared with the existing evidence. No patients developed severe symptomatic VTE, and only two patients (1.9%) developed asymptomatic VTE. This high treatment efficacy is comparable with that in a previous prospective randomized trial of postoperative pharmacologic thromboprophylaxis with enoxaparin after curative abdominal or pelvic cancer surgery [9], and in another trial of perioperative unfractionated heparin for colorectal surgery [27] (Table 3). In the former study, the incidence of VTE in the patients treated with enoxaparin was 1.2% [9]. In the latter study, the incidence of VTE was 1.6%e3.6% [27]. The secondary endpoint of the present study was the incidence of all postoperative adverse events. Eleven patients (10.7%) developed a grade B or C POPF; however, no in-hospital mortality occurred. Moreover, the incidence of postoperative hemorrhage (4.9%) in this study was comparable with not only a previous prospective trial of enoxaparin after surgical treatment of abdominal or pelvic cancer (9.2%) [9], but also previous retrospective studies of postpancreatectomy hemorrhage (about 6%e8%) [11,14e16,28] (Table 3). The cases of major bleeding in the present study were associated with POPF, and the affected patients immediately recovered after intervention. These results may indicate that administration of enoxaparin after pancreatic surgery does not increase the risk of postoperative bleeding. There were some limitations in this study. First, this was a
Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010
D. Hashimoto et al. / Pancreatology xxx (2017) 1e7
single-arm trial and the sample size may be small to draw the conclusion in this study, because incidence of DVT as primary endpoint and post-operative hemorrhage as secondary endpoint were less than 5%. Further randomized studies including at least 200e300 patients should be designed to compare enoxaparin with other types of pharmacologic thromboprophylaxis to evaluate less incidence of endpoints. Second, our study included 15 patients (14.6%) who underwent laparoscopic surgery, and none developed VTE. Although a previous meta-analysis indicated that the incidence of postoperative VTE was not significantly different between laparoscopic versus open surgery for colorectal disease [29], this topic has not been adequately discussed in pancreatic surgery and should be analyzed in the future. Third, our study did not routinely evaluate the D-dimer concentration. Some studies have shown that D-dimer measurement is effective for screening of DVT [30,31]. However, other studies have indicated that the benefit of D-dimer testing is limited to ruling out VTE [32]. The efficacy of preoperative D-dimer testing should be analyzed and discussed in the future. Fourth, we performed enhanced CT on postoperative day 6 ± 1 and color Doppler ultrasonography 1 day after the final administration of treatment to identify VTE. The methods of identifying VTE differ among studies [9,27]. The efficacy of each method used to evaluate postoperative VTE should be compared in a future study. In conclusion, this is the first prospective trial to focus on pharmacologic prophylaxis with enoxaparin after pancreatic surgery. The results of this single-center, single-arm prospective study indicate that enoxaparin may prevent VTE in the majority of patients undergoing pancreatectomy without increasing the incidence of adverse events, such as postoperative bleeding, compared with existing evidence. These findings should be confirmed in further studies including more patients.
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Acknowledgments
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The authors have no conflicts of interest to declare. No funding was received for this study.
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Please cite this article in press as: Hashimoto D, et al., Efficacy and safety of postoperative anticoagulation prophylaxis with enoxaparin in patients undergoing pancreatic surgery: A prospective trial and literature review, Pancreatology (2017), http://dx.doi.org/10.1016/ j.pan.2017.03.010