Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons

DOI:10.1111/hpb.12278 HPB ORIGINAL ARTICLE Venous thromboembolic prophylaxis after a hepatic resection: patterns of care among liver surgeons Matthew J. Weiss, Yuhree Kim, Aslam Ejaz, Gaya Spolverato, Elliott R. Haut, Kenzo Hirose, Christopher L. Wolfgang, Michael A. Choti & Timothy M. Pawlik Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract Introduction: No consensus exists for post-hepatectomy venous thromboembolic (VTE) prophylaxis. Factors impacting VTE prophylaxis patterns among hepato-pancreato-biliary (HPB) surgeons were defined. Method: Surgeons were invited to complete a web-based survey on VTE prophylaxis. The impact of physician and clinical factors was analysed. Results: Two hundred responses were received. Most respondents were male (91%) and practiced at academic centres (88%) in the United States (80%). Surgical training varied: HPB (24%), transplantation (24%), surgical oncology (34%), HPB/transplantation (13%), or no specialty (5%). Respondents estimated VTE risk was higher after major (6%) versus minor (3%) resections. Although 98% use VTE prophylaxis, there was considerable variability: sequential compression devices (SCD) (91%), unfractionated heparin Q12h (31%) and Q8h (32%), and low-molecular weight heparin (39%). While 88% noted VTE prophylaxis was not impacted by operative indication, 16% stated major resections reduced their VTE prophylaxis. Factors associated with the decreased use of pharmacologic prophylaxis included: elevated international normalized ratio (INR) (74%), thrombocytopaenia (63%), liver insufficiency (58%), large EBL (46%) and complications (8%). Forty-seven per cent of respondents wait until post-operative day 1 (POD1) and 35% hold pharmacologic VTE prophylaxis until no signs of coagulopathy. A minority (14%) discharge patients on pharmacologic prophylaxis. While 81% have institutional VTE guidelines, 79% believe hepatectomy-specific guidelines would be helpful. Conclusion: There is considerable variation regarding VTE prophylaxis among liver surgeons. While most HPB surgeons employ VTE prophylaxis, the methods, timing and purported contraindications differ significantly. Received 16 February 2014; accepted 22 April 2014 Correspondence Matthew J. Weiss, Department of Surgery, Johns Hopkins Hospital, 600 N. Wolfe Street, Halsted 608, Baltimore, MD 21287, USA. Tel: +1 410 614 368. Fax: +1 410 614 9493. E-mail: mweiss5@jhmi.edu Introduction The development of venous thromboembolism (VTE) in the perioperative period can be a devastating complication with high morbidity and mortality. Strategies to prevent the development of VTE include sequential compression devices (SCD) and pharmacologic VTE prophylaxis. The use of pharmacologic VTE This manuscript was presented at the 2014 Americas Hepato-Pancreato- Biliary Association Conference, Miami, 21 February 2014. prophylaxis can reduce the incidence of deep vein thrombosis (DVT) and (pulmonary embolism) PE by about 75% among general surgery patients. 1,2 For the majority of abdominal operations, peri-operative pharmacological VTE prophylaxis is now considered the standard of care for patients with a moderate-tohigh risk of developing a VTE. 3,4 Most patients undergoing a liver resection would be considered moderate-to-high risk, 5 as VTE within 90 days of a hepatic resection has been reported to occur in nearly 1 in 12 patients. 6,7 Liver surgeons, however, are often worried about the potential for post-operative haemorrhage after

HPB 893 a hepatectomy and may not be inclined to utilize peri-operative pharmacological VTE prophylaxis. The decision whether to employ peri-operative VTE prophylaxis, and the type of prophylaxis (e.g. SCDs vs. pharmacologic VTE prophylaxis), often relies on the individual surgeons assessment of the relative risk of developing a VTE versus post-operative haemorrhage for a particular patient and operation. Further complicating a liver surgeon s decision on prophylaxis are the numerous available types of VTE prophylaxis [SCD, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH)], as well as the varied dosing interval associated with pharmacological VTE prophylaxis (e.g. q 12 h vs. q 8 h). Historically, some surgeons have perceived the risk of VTE after a liver resection to be lower than for other major abdominal procedures owing to transient liver dysfunction sometimes reflected in an increased prothrombin time and international normalized ratio (INR). Barton et al. 8 found, however, that in spite of elevated INR values, thromboelastography actually demonstrated a brief hypercoagulable state after a liver resection. Other studies have similarly noted that VTE risk may actually increase with more extensive hepatic resections even in the setting of increased post-operative INR levels. 9,10 Even patients suffering from chronic liver insufficiency do not appear to be anticoagulated based on elevated INR levels and may actually be at an increased risk of VTE. 11,12 Owing to a lack of data on VTE-related outcomes after a hepatectomy, current practice guidelines regarding prophylaxis for patients undergoing a liver resection remain unclear. While some institutions have formalized current best practices around prophylaxis for VTE after a hepatic resection, other centres have not. Although there is a perceived large amount of heterogeneity in practice patterns among liver surgeons, the degree of this variability has not been previously defined or quantitated. In the present study, we hypothesized that a wide array of factors might influence the choice of whether to administer VTE prophylaxis around the time of a hepatic resection. We sought to determine current VTE prophylaxis patterns among practicing hepatopancreato-biliary (HPB) surgeons and define what clinical factors impact their choice and timing of VTE prophylaxis. Methods Key clinical factors were incorporated into a 35-question survey that was designed to evaluate current VTE prophylaxis patterns among surgeons who perform liver surgery (Appendix S1). The survey instrument was divided into three sections focused on data collection regarding: (i) details on surgeon demographics and training, (ii) surgeon perception and assessment of VTE risks, practice patterns and opinions on VTE prophylaxis utilization, and (iii) VTE guidelines. In particular, the respondent was asked which VTE prophylaxis (s)he would recommend around the time of liver resection, when prophylaxis is typically initiated, as well as the type of prophylaxis preferred (e.g. SCD, UFH, LMWH). In addition, specific questions were aimed at identifying which clinical factors the respondent utilized in making decisions regarding VTE prophylaxis at the time of liver resection. The clinical factors which we asked respondents to evaluate for a potential impact on VTE prophylaxis included: a prior history of DVT/ PE, hypercoaguable diagnosis, obesity, cancer diagnosis, co-morbidities, combined operations, post-operative complications, elevated INR values, liver insufficiency, large volume blood loss and major versus minor liver resections. All co-authors reviewed the survey for validity and we did a small pilot of sending the survey to all HPB faculties in the participating departments. Invitations to take the survey were sent by e-mail to surgical members of the Americas Hepato-Pancreatobiliary Association, International Hepato-Pancreatobiliary Association and Surgical Society of the Alimentary Tract, with self-reported interests in liver surgery; e-mail addresses were obtained from publicly available sources such as web sites and publications in the field. 13,14 Response to the survey was voluntary and anonymous; no financial incentive was offered to encourage participation. After the initial distribution of the survey, we scheduled three automatic email reminders at 2-week intervals to all non-responders, which were coded with a unique identification number. The survey was sent to 414 email addresses and opening the email was considered confirmation that the email address was correct and the survey was viewed. The questionnaire was available online through QuestionPro (a survey engine). The study protocol and survey instrument were approved by the Johns Hopkins University School of Medicine Institutional Review Board. 35-question survey Descriptive statistics were compared using Fisher s exact test, the rank-sum test, or the Kruskal Wallis test, as appropriate. Choice data were analysed using multinomial logistic regression models with robust variance estimates, yielding odds ratios (OR) and 95% confidence intervals (95% CI) that reflect the change in the odds of choosing a particular therapy over an alternative. For each of the 10 different VTE prophylaxis patterns examined a separate regression model was created that included factors of clinical significance including: gender, country of practice, private or community hospital vs. academic or university hospital, fellowship, years after training and practice pattern. All tests of statistical significance were two-sided, and statistical significance was established at P < 0.05. Statistical analyses were performed using Stata/MP 10.1 for Windows (StataCorp LP, College Station, TX, USA). Results The email was sent to 414 recipients, 297 recipients opened the email, and 200 responded. Demographic and practice characteristics of the respondents are given in Table 1. The majority of respondents (88%) practiced at academic centres, and 55% were in practice 10 years. The overwhelming majority of respondents were male (91%) and practiced in the United States (81%). Surgical training varied: 34% surgical oncology, 24% transplant,

894 HPB Table 1 Surgeon demographics and practice characteristics of respondents (n = 200) Characteristics Value, No. (%) Male gender, No. (%) 181 (91) Country, US, No.(%) 161 (81) Fellowship, No.(%) Surgical Oncology Fellowship 68 (34) Hepato-Pancreato-Biliary Fellowship 48 (24) Transplant Fellowship 48 (24) Combined hepato-pancreato-biliary and 25 (13) Transplant Fellowship None 11 (6) Years after completion of training, No.(%) 10 years 91 (46) 11 20 years 65 (33) 21 30 years 34 (17) >30 years 10 (5) Primary practice setting, No.(%) Academic practice or university hospital staff 175 (88) Private practice or community hospital staff 24 (12) Hepato-pancreato-biliary practice 75% 93 (47) 50 74% 40 (20) 25 49% 34 (17) <25% 33 (17) Number of liver resection per month, median (IQR) 4 (2 5) Major resection( 3 segments), %, median (IQR) 50 (34 70) IQR, interquartile range. Table 2 Method and timing of respondents' VTE prophylaxis patterns Type of DVT/PE prophylaxis (multiple choice) No. (%) Sequential compression devices 176 (91.2) Low molecular weight heparin 76 (39.4) Unfractionated heparin q8 hours 61 (31.6) Unfractionated heparin q12 hours 59 (30.6) Time of administering DVT/PE prophylaxis No. (%) POD 0 103 (53.4) POD 1 90 (46.6) Hold administering of pharmacologic DVT/PE (%) prophylaxis until laboratory values demonstrate no signs of coagulopathy or bleeding Strongly agree and Agree 34.2 Neither agree nor disagree 13.8 Strongly disagree and Disagree 52.0 VTE, venous thromboembolic; DVT, deep vein thrombosis; PE, pulmonary embolism, POD, post-operative day. 24% HPB, 13% combined HPB/transplant and 5% no fellowship training. Most respondents (67%) reported that the majority (>50%) of their clinical practice involved HPB surgery. Respondents reported performing a median of four [interquartile range (IQR) 2 5] liver resections per month, with half (50%) of the resections being major ( 3 segments) (IQR 34 70). Responses to attitudinal questions of respondents regarding the method and timing of VTE prophylaxis patterns were assessed. The overwhelming majority (98%) of respondents routinely used VTE prophylaxis. There was considerable variability, however, regarding which VTE prophylaxis modalities were employed: 91% SCD, 39% LMWH, 32% UFH every 8 h and 31% UFH every 12 h (Table 2). When asked to assess the risk of VTE among patients undergoing a liver resection, respondents had a variable estimate. Specifically, 4% of respondents estimated the risk to be <1%, whereas 69% estimated the risk at 1 6%, 17% at 7 9%, and 10% thought the risk of VTE after liver resection was >10%. Of note, respondents estimated the risk of VTE to be higher after a major versus minor resection (mean estimated risk: 7% vs. 4%, respectively; P < 0.001). In spite of this, 16% of respondents noted that they were less likely to administer pharmacological VTE prophylaxis after a major resection compared with a minor resection. In general, respondent estimates for VTE risk varied based on the indication for surgery: benign (2%) vs. malignant (5%) disease (P < 0.001). However, 88% of respondents stated that the likelihood of administering pharmacological VTE prophylaxis did not change based on the indication for surgical resection. Factors that most respondents did state would increase their likelihood of administering pharmacological VTE prophylaxis after a hepatectomy included: a history of DVT/PE (89%), a hypercoaguable diagnosis (88%), obesity (84%), multiple medical co-morbidities (67%), combined operations (65%) and early post-operative complications other than haemorrhage (38%) (Fig. 1). In contrast, factors that influenced respondents to choose not to use pharmacological VTE prophylaxis included: elevated INR (74%), thrombocytopaenia (63%), liver insufficiency (58%), large operative blood loss (46%) and an early post-operative complication (7%) (Fig. 2). With regard to the timing of pharmacological VTE prophylaxis initiation, 47% of respondents reported that they routinely waited until post-operative day (POD) 1 or longer and 35% stated that they routinely hold pharmacological VTE prophylaxis until there are no objective signs of coagulopathy. While only 17% of respondents indicated that they believe pharmacological VTE prophylaxis increased the risk of post-operative bleeding, 15% stated that they have had at least one bleeding complication that they believe was directly attributable to pharmacological VTE prophylaxis administration. Among all respondents, 28% reported that they believed routine administrative of pharmacological VTE prophylaxis pre-operatively was unnecessary; this proportion increased to 59% when respondents were asked about patients undergoing only a minor liver resection. Twenty-two per cent of respondents stated that their VTE prophylaxis pattern changed based on the extent of liver resection.

HPB 895 (%) 100 90 80 70 60 50 40 30 20 10 0 Previous history of DVT/PE Hypercoaguable diagnosis Obesity Cancer diagnosis Multiple comorbidities Combined operations Early postoperative complication other than haemorrhage Figure 1 Proportion of respondents identifying factor as increasing likelihood of administering pharmacological deep vein thrombosis (DVT)/pulmonary embolism (PE) prophylaxis 100 90 80 70 60 50 40 30 20 10 0 Elevated Thrombocytopaenia Liver Large volume Major liver Early INR insufficiency blood loss resection post-operative complication other than haemorrhage Figure 2 Proportion of respondents identifying factor as decreasing likelihood of administering pharmacological deep vein thrombosis (DVT)/pulmonary embolism (PE) prophylaxis (%) Of note, 14% of respondents noted that they routinely discharge patients home on pharmacological VTE prophylaxis after hepatic resections. Surgeon-specific factors were evaluated for differences in selfreported practice patterns regarding thromboembolic prophylaxis. While there were no differences in timing of pharmacological VTE prophylaxis associated with surgeon demographics or training experience, self-reported surgeon HPB volume influenced pharmacological VTE prophylaxis practice patterns. Compared with lower volume HPB surgeons, surgeons who described their practice as >75% HPB estimated that the risk of VTE was lower for both minor (5% vs. 3%, respectively; P < 0.001) and major hepatectomies (8% vs. 6%, respectively; P = 0.01) (Table 3). In addition, compared with lower volume HPB surgeons, surgeons who self-reported a practice consisting of >75% HPB cases stated using pharmacological VTE prophylaxis a mean duration of 1.5 days longer (4.6 vs. 6.1 days, P = 0.03) after a liver resection. Attitudes towards pharmacological VTE prophylaxis were also impacted by factors such as academic versus community hospital status, as well as geographical location of the provider. Specifically, surgeons who practiced in a community setting were more likely to believe that the administration of

896 HPB Table 3 Clinical factors associated with patterns of VTE prophylaxis use among hepato-pancreato-biliary surgeons Patterns of VTE prophylaxis OR 95% CI P-value Hold prophylaxis administration until there are no signs of coagulopathy Clinical care >75% Ref Clinical care 75% 0.55 0.30 1.01 0.05 Send patients home on pharmacological prophylaxis US surgeon 0.37 0.15 0.87 0.02 Clinical care >75% Ref Clinical care 75% 3.82 1.54 9.48 0.004 Sequential compression US surgeon 3.62 1.47 8.94 0.005 Unfractionated heparin q12 11 20 years 1.59 0.78 3.24 0.20 21 30 years 2.33 1.01 5.40 0.05 >30 years 1.43 0.34 6.02 0.63 Unfractionated heparin q8 US surgeon 4.80 1.62 14.17 0.005 11 20 years 0.37 0.18 0.75 0.01 21 30 years 0.29 0.11 0.76 0.01 >30 years 0.33 0.07 1.66 0.18 LMWH US surgeon 0.38 0.19 0.77 0.008 Administering prophylaxis increases the risks of surgical bleeding Private practice or community hospital Ref Academic practice or university hospital 0.15 0.06 0.38 <0.001 Postoperative prophylaxis is necessary Major resection >51% Ref Major resection 50% 0.22 0.08 0.62 0.004 All patients should receive prophylaxis before and after liver resection US surgeon 2.28 1.06 4.90 0.04 11 20 years 0.59 0.27 1.28 0.18 21 30 years 0.31 0.13 0.76 0.01 >30 years NA Patients undergoing a minor liver resection should receive both pre and post operative prophylaxis 11 20 years 0.68 0.35 1.32 0.25 21 30 years 0.38 0.17 0.84 0.02 >30 years 0.24 0.06 1.02 0.05 Each of the 10 statistical regression models the same independent variables which include gender, country of practice, private or community hospital vs. academic or university hospital, fellowship, years after training, and practice pattern. VTE, venous thromboembolic; LMWH, low-molecular-weight heparin; US, United States; OR, odds ratio; CI, confidence interval. pharmacological VTE prophylaxis increased the risk of postoperative surgical bleeding (OR 6.77, 95% CI 2.66 17.22; P < 0.001). Furthermore, surgeons practicing in the United States were more likely to use SCD (OR 3.62, 95% CI 1.47 8.94; P = 0.005), as well as UFH every 8 h as pharmacological VTE prophylaxis (OR 4.80, 95% CI 1.62 14.17; P = 0.005). In contrast, surgeons from the United States were less likely to report using LMWH as pharmacological VTE prophylaxis (OR 0.38, 95% CI 0.19 0.77; P = 0.008). United States surgeons were also less likely to report the practice of discharging patients home on pharmacological VTE prophylaxis after hepatic resections (OR 0.37, 95% CI 0.15 0.87; P = 0.02). Regarding general attitudes about VTE guidelines and practice patterns at their hospital, 88% of respondents reported a belief that a major variation in pharmacological VTE prophylaxis patterns existed among HPB surgeons. Most respondents (81%) indicated that their own institution had guidelines on VTE prophylaxis and most surgeons (80%) reported adherence to the recommended hospital guidelines. However, only 52% of respondents believed that their institutional VTE guides were actually based on data relevant for patients undergoing HPB surgery and 79% of respondents stated that consensus guidelines specific for a hepatectomy would be useful in their practice. Discussion Liver surgeons face a challenging dilemma in deciding on the method and timing of VTE prophylaxis after a hepatectomy. Several recent studies have demonstrated that the occurrence of VTE after a hepatectomy is not uncommon and the incidence ranges from 2.1% to 4.7%. 6,9,10,15 18 In the past, liver surgeons have been reluctant to initiate pharmacological prophylaxis because of the perception that these patients may be at a lower risk of developing VTE events and a higher risk of post-operative bleeding than other surgical procedures. However, a review of 5651 NSQIP patients undergoing liver surgery revealed that the risk of VTE was higher after major hepatic resections and outweighed the risk of bleeding. 10 In fact, these investigators found that patients who experienced a VTE had a 30-day mortality of 7.4% versus 2.3% for those patients who did not have a VTE event. 10 The American College of Chest Physicians has recommended the use of chemoprophylaxis over no prophylaxis in surgical patients of moderateto-high risk. 3 In turn, based on the widely used and externally validated Caprini risk scoring system, most patients undergoing a liver resection would be considered moderate-to-high risk. 5 However, owing to the perceived risk of possible peri-operative bleeding after a hepatectomy, this recommendation is only grade 2C. 19,20 Provider perceptions about these guideline recommendations, as well as surgeon VTE practice patterns, have been poorly characterized. The current study is important because it utilized a broad-based multi-institutional survey to define surgeon attitudes and practices around VTE prophylaxis after a liver resection. We found that considerable practice variation exists among liver

HPB 897 surgeons. Interestingly, while 98% of surgeons routinely use VTE prophylaxis, the methods and timing of pharmacological VTE prophylaxis varied significantly. While most surgeons utilized SCDs (91%) in combination with pharmacological VTE prophylaxis, some employed UFH (61%) and others LMWH (39%). The reported high frequency use of combined pharmacological VTE prophylaxis and SCDs in our study is in agreement with current recommendations against mechanical methods as monotherapy for cancer patients. 21 Regarding the choice of pharmacological VTE prophylaxis, there are three randomized trials comparing LMWH and UFH for pharmacological VTE prophylaxis in cancer 22,23 and colorectal surgery 24 patients, all of whom appear to show similar efficacy with LMWH and UFH. However, meta-analyses evaluating different dosing regimens of these drugs demonstrate that UFH given every 8 h, as well as daily LMWH, are superior to UFH given twice daily. 2,25 This is noteworthy, because roughly one-third of respondents are utilizing UFH twice daily. There are no studies evaluating the optimal timing of pharmacological VTE prophylaxis for hepatectomies; however, current international guidelines for patients undergoing cancer surgery recommends initiation of pharmacological VTE prophylaxis 2 12 h pre-operatively. 21 A large proportion of respondents do not appear to be following these guidelines for patients undergoing a hepatectomy; 47% of respondents stated that they routinely wait until POD 1 and 35% until there are no signs of coagulopathy before initiating pharmacological VTE prophylaxis. Similarly, in spite of data to suggest that the risk of VTE remains elevated for at least 12 weeks after surgery, 3 only 14% of liver surgeons routinely send patients home on pharmacological VTE prophylaxis. This may be important because Tzeng et al. 17 found that 29% of all VTE after a hepatectomy occurred post-discharge. Based upon somewhat limited data, the authors currently initiate mechanical and pharmacological VTE prophylaxis within 2 h of incision and continue pharmacological VTE prophylaxis for the duration of the hospitalization after a hepatectomy. However, given the significant variation found in prophylaxis patterns amongst liver surgeons in this survey, we sought to identify factors that might influence provider decisions around VTE administration. We found that significant practice variation exists that is independent of post-graduate training and several other demographical variables. Self-reported higher volume HPB surgeons described the risk of VTE as lower, while stating that they prescribe pharmacological VTE prophylaxis for a longer duration than lower volume HPB surgeons. In addition, surgeons in community practice were more likely to believe that pharmacological VTE prophylaxis increased the risk of bleeding after a hepatectomy. Interestingly, surgeons from the United States more frequently used UFH for pharmacological VTE prophylaxis and were less likely to continue therapy post-discharge. Our study had several limitations which should be considered. First, the survey assessed stated preferences for VTE prophylaxis among liver surgeons as opposed to their actual practice patterns. There may be differences between a surgeon s stated and actual VTE prophylaxis pattern. Second, because we do not know the characteristics of the non-respondents, we cannot verify that the findings are representative of all surgeons performing hepatectomies. We specifically targeted surgeons who had publically available email addresses, so our results may not be representative of liver surgeons at-large. However, the demographics of respondents reflected a wide range of training backgrounds and 19% of respondents were from outside of the United States. In conclusion, there is considerable practice variation regarding VTE prophylaxis among liver surgeons. The vast majority of surgeons agree that VTE events after a hepatectomy are not uncommon and routinely employ VTE prophylaxis. However, the methods, timing and purported contraindications to VTE prophylaxis differ significantly among liver surgeons and are not necessarily supported by the literature. Different VTE prophylaxis patterns appear independent of post-graduate training and most demographic variables, but may be related to reported volume of HPB surgery, practice setting and location. 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