- Email: [email protected]
Perception of Chemical Venous Thromboprophylaxis for Oncologic Lung Resections among Thoracic Surgeons
Clinical Research Perception of Chemical Venous Thromboprophylaxis for Oncologic Lung Resections among Thoracic Surgeons Rafael D. Malgor,1 Thomas V. Bilfinger,2 John Blebea,1 Harry Ma,1 and Shirliejean R. Arnold,1 Tulsa, Oklahoma and Stony Brook, New York
Background: Controversies on chemical venous thromboembolic (VTE) prophylaxis in patients undergoing lung resection for malignancy exist. The available guidelines on VTE do not specifically address its prophylaxis in patients undergoing oncologic lung resections. The goal of this survey was to evaluate the perception of VTE prophylaxis among thoracic surgeons performing these operations. Methods: A self-reported online survey was distributed to 267 active members of the General Thoracic Surgical Club between July and September 2015. The survey consisted of 22 questions related to the use of chemical venous thromboprophylaxis in patients undergoing oncologic lung resection and their impact on outcomes. Results: Fifty-six thoracic surgeons replied to the survey. The majority of these surgeons (57%) perform both open and thoracoscopic surgery for lung cancer. All respondents stated that treatment modality and extent of surgical resection have no influence on their decision to use chemical VTE prophylaxis. Twenty-two (39%) respondents do not use chemical VTE prophylaxis prior to their oncologic lung resections, while the remaining 34 (61%) reported use of anticoagulants prior to them. None of the respondents prescribe extended 30-day VTE prophylaxis to these patients. Forty-nine (87%) respondents believe that chemical VTE prophylaxis is not related to major postoperative bleeding episodes. Forty-five (81%) respondents reported that none of their reoperations for bleeding were secondary to VTE prophylaxis or if it was, that isolated event could be successfully managed nonoperatively. Conclusions: The majority of thoracic surgeons surveyed believe that chemical VTE prophylaxis is safe and should be used regardless of the magnitude of oncologic lung resections whenever possible. Extended 30-day VTE prophylaxis is not yet used by the survey respondents.
INTRODUCTION 1
Division of Vascular Surgery, Department of Surgery, The University of Oklahoma, Tulsa, OK. 2 Division of Cardiothoracic Surgery, Department of Surgery, Stony Brook University Medical Center, Stony Brook, NY.
Correspondence to: Rafael D. Malgor, MD, Division of Vascular Surgery, Department of Surgery, The University of Oklahoma, 1919 S. Wheeling Avenue, Suite 600, Tulsa, OK 74133, USA; E-mail: [email protected] Ann Vasc Surg 2017; -: 1–8 http://dx.doi.org/10.1016/j.avsg.2017.03.188 Ó 2017 Elsevier Inc. All rights reserved. Manuscript received: April 7, 2016; manuscript accepted: March 2, 2017; published online: - - -
Venous thromboembolism (VTE) remains an important cause of morbidity and mortality in patients with cancer.1e3 Patients undergoing oncologic lung resection are at high risk of pulmonary embolism (PE) and deep vein thrombosis (DVT).4 Recently, several systematic reviews have emphasized the importance of knowing the incidence of VTE in this cohort of patients and the impact of chemical thromboprophylaxis.5,6 Nonetheless, the use of VTE prophylaxis and its currently used regimens in this subset of patients remains vastly unknown. 1
2 Malgor et al.
Current guidelines recommend that patients undergoing oncologic resection must receive chemical VTE prophylaxis with unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) plus mechanical thromboprophylaxis whenever possible provided the risk of bleeding is not high.7,8 However, these guidelines are mainly based on data from patients with abdominopelvic malignancies. Recommendations on VTE prophylaxis exist for patients undergoing thoracic surgery, but they are not specific for oncologic thoracic patients. In addition, the level of evidence varies widely when it comes to recommending chemical, mechanical, a combination of both, or no prophylaxis for nononcologic patients.7 These recommendations rely on perioperative risk of bleeding which is often difficult to gauge and on VTE risk stratification using validated assessment tools (e.g. Caprini scores), which are not a daily routine in several centers performing thoracic surgery.7 For instance, gauging the risk of bleeding prior to lung resections is cumbersome especially in certain cases when pneumonectomies or en bloc resection for bronchogenic carcinoma with chest wall involvement is performed. Little is known about the adherence and perception of thoracic surgeons of chemical VTE prophylaxis and its complications as well as morbidity and mortality related to VTE in their practices. The purpose of this research is to understand the perception and current practice among thoracic surgeons of chemical VTE prophylaxis when dealing with patients undergoing lung resection for cancer.
METHODS Population Selection and Survey Distribution Members of the General Thoracic Surgical Club (GTSC) were invited to participate in an online survey about chemical VTE prophylaxis in patients undergoing surgery for lung cancer. The GTSC was founded in 1986 and is composed of only boardcertified surgeons by the American Board of Thoracic Surgery whose practice consists of at least 50% of general thoracic surgery. Currently, the GTSC has 267 active members. Approval from the University of Oklahoma institutional review board (Committees on Research Involving Human Subjects) was obtained prior to launching the survey. The electronic contact mail information of GTSC members was never available to the researchers; instead, the GTSC secretariat was responsible to distribute the survey in order to
Annals of Vascular Surgery
prevent identification of respondents. Electronic surveys were created using QualtricsÔ (Qualtrics, Provo, UT), an online ballot tool. All responses were received anonymously. GTSC members who have been retired for more than 10 years were excluded from analysis. This was a voluntary survey, which was distributed initially at the end of July 2015. A welcoming survey email was sent to all GTSC members containing a brief description of project goals along with a hyperlink to access the electronic, web-based survey. All active members of the GTSC were initially emailed, but only 33 responses were recorded after the first attempt. A second email was sent 4 weeks later, the number of respondents then reached 56. The last reminder was sent 8 weeks after the first welcoming survey email, but this last attempt failed to increase the number of respondents. Responses were collected up to the last day of September 2015. Questionnaire Description Twenty-two multiple choices questions were formulated to evaluate preoperative and postoperative use of chemical VTE prophylaxis among thoracic surgeons who often perform oncologic lung resection. The first 6 questions were designed to gather demographic data, type of practice, geographic location, and years in practice. The following 3 questions were formulated to assess type of procedures and overall number of lung resections performed/year. Questions 10e14 emphasize the VTE prophylaxis regimens used by thoracic surgeons and its characteristics, such as preferred anticoagulants and their posology. Questions 15e21 were formulated to investigate morbidity and mortality related to VTE prophylaxis, such as bleeding, DVT, PE, and death rate encountered by surgeons in their practices. The closing question was focused on gathering information about the thoracic surgeons’ receptivity to a specific guideline on VTE prophylaxis and lung surgery shall it becomes available in the near future. Statistical Analysis Descriptive data are reported as proportion of respondents providing a particular survey response. Statistical comparison between proportions was performed when appropriate. Student’s t-test was utilized to compare continuous variables and chi-squared test to compare categorical variables. A value of P < 0.05 was used for determination of statistical significance. The Statistical Package for Social Sciences v.18.0 was utilized for analysis (SPSS Inc., Chicago, IL).
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Table I. Demographics and geographic location of survey respondents’ thoracic practice Variables
Age (years) Under 30 30e39 40e49 50e59 60e69 70 or greater Total Gender Male Female Total Practice location Northeast (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont, New Jersey, New York, and Pennsylvania) Midwest (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin) South (Delaware, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, Washington D.C., West Virginia, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana, Oklahoma, and Texas) West (Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, Wyoming, Alaska, California, Hawaii, Oregon, Washington) Outside the United States Total
RESULTS Response Rate and Demographics The response rate accounted for 21% of the active GTSC members. The majority of respondents reported practices in the Northeast (N ¼ 19, 34%) followed by the Midwest (N ¼ 15, 27%). Three (5%) out of 56 respondents reported practices outside of the United States, 2 in Canada, and 1 in Italy. There was a significant discrepancy between genders with more male respondents than females. Further details of demographic and geographic location of survey respondents’ practice are shown in Table I. Years of Experience, Practice Patterns, and Scope of Practice All respondents but 2 had greater than 6 years of experience in treating lung cancer. Six respondents were not currently practicing by the time they answered this survey; however, they have been retired for less than 10 years. Fifty (89%) surgeons have careers entirely focused on thoracic surgery,
N
%
0 2 17 21 9 7 56
0 4 30 37 16 13 100
51 5 56
91 9 100
19
34
15
27
12
21
7
13
3 56
5 100
3 (5.5%) others practice cardiac and thoracic surgery, and the remaining 3 (5.5%) surgeons have a mixed thoracic, cardiac, and peripheral vascular surgery practice. The majority of surgeons (57%) perform both open and thoracoscopic surgery for lung cancer. All respondents stated that treatment modality and extent of surgical resection have no influence on their decision to administer chemical VTE prophylaxis to their patients with lung cancer (P ¼ NS). Table II depicts thoracic practice patterns, annual case volume of lung resections, and preferred surgical treatment modalities when dealing with patients with lung cancer. Preferences on Preoperative and Postoperative Use of Chemical VTE Prophylaxis Twenty-two (39%) respondents reported that they do not use VTE prophylaxis prior to wedge resections, lobectomies, or pneumonectomies, while the remaining 34 respondents reported use of either UFH (N ¼ 30, 54%) or LMWH (N ¼ 4, 7%) prior to
4 Malgor et al.
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Table II. Practice pattern, preferred surgical modality and annual case volume Variables
Practice pattern Academic practice Private practice with an affiliated teaching program Private practice with no resident or fellow interaction Total Preferred surgical treatment modality for lung cancer I am an open surgeon, I never do lung resections for cancer thoracoscopically or robotically I perform both open and thoracoscopic lung cancer resections I predominantly do lung cancer surgery thoracoscopically, rarely open, never robotically I predominantly do lung cancer surgery thoracoscopically or robotically, never open I do pneumonectomies and lobectomies open, but wedge resections thoracoscopically Total Lung resections for lung cancer/year 0e9 10e29 30e49 50e100 >100 Total
any oncologic lung resections. Surgeons who always use chemical VTE prophylaxis stated that the extent of lung resection, such as pneumonectomies, does not play a role in their decision to use VTE prophylaxis. Three quarters of those who prefer to use subcutaneous UFH prior to surgery use 5000 units every 8 hr as a postoperative prophylaxis regimen; the remaining quarter of respondents prefer to use the same amount of UFH, but every 12 hr. All respondents who use UFH also stated that the first postoperative prophylaxis dose is given within 8 hr after surgery, while those who use LMWH wait until the next day to redose it. There was a trend toward using UFH over LMWH based on longer years in practice (P ¼ 0.05). Surgeons were then asked if they would change their strategy regarding postoperative VTE prophylaxis if the procedure had more intraoperative bleeding than expected. Thirteen (23%) surgeons answered they would hold chemical VTE prophylaxis for at least 24 hr postoperatively based on their purely personal preferences which are not based on evidence-based data. When respondents were asked if they prescribe any VTE prophylaxis upon discharge from the hospital based on patients’ VTE risk factors (i.e., lung cancer, surgery, immobility), the majority of surgeons stated that they do not prescribe any chemical VTE prophylaxis after discharging patients
N
%
37 10 9 56
66 18 16 100
2
4
32 12
57 21
5
9
5
9
56
100
1 5 9 25 16 56
2 9 16 45 28 100
from the hospital. VTE prophylaxis practices and patterns after discharge from hospital are depicted in Fig. 1. Complications Related to Chemical VTE Prophylaxis Forty-nine (87%) respondents believe that chemical VTE prophylaxis is safe and it is not related to any additional postoperative bleed their patients have had in the past. Two (4%) respondents believe that chemical VTE prophylaxis has been the cause of a postoperative bleed, which has made them refrain from using it in their major oncologic resections. The remaining 5 (9%) surgeons reported a few postoperative bleeding events they believe have been secondary to the use of prophylactic heparin given preoperatively and/or postoperatively; however, regardless of the impression of increased risk of postoperative bleed related to chemical thromboprophylaxis, these 5 surgeons continue to use it in order to prevent DVT and PE. When asked if a reoperation had to be performed due to postoperative bleed, which was believed to be secondary to administration of chemical VTE prophylaxis, 7 (12%) surgeons reported no correctable surgical causes found during reoperation and another 4 (7%) stated the bleed was secondary to a bleeding vessel. The majority of remaining
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Venous thromboprophylaxis and oncologic chest surgery 5
Fig. 1. Use of chemical thromboprophylaxis after discharge from hospital.
surgeons (81%) reported they either believed that none of their reoperations for bleeding were secondary to VTE prophylaxis or that whenever a postoperative bleed occurred and it was deemed to be related to VTE prophylaxis, that specific event was successfully managed nonoperatively. Incidence of VTE and Its Morbidity and Mortality The respondents were asked if they recalled any episodes of DVT or PE in patients who underwent oncologic lung resection that occurred over the past 2 years. Twenty-three (41%) respondents answered that no episodes of VTE have occurred in this time span. Twenty-six (46%) surgeons recalled at least 1e2 episodes of VTE over the past 2 years, and 7 (13%) reported at least 3e5 cases of VTE in their practice. None of the respondents stated more than 5 episodes of VTE over the past 2 years in practice regardless of an available alternative in the survey stating VTE occurrence greater than 5 episodes. Surgeons were finally questioned about the percentage rate of DVT over the years in their cohort of oncologic patients undergoing lung resection (Fig. 2A) and if they believed that the patients were on VTE prophylaxis when they developed a DVT (Fig. 2B). They were also asked how many of their patients had died from PE within 30 days from an index oncologic lung resection over the past 10 years. Thirty-one (55%) answered none of their patients have ever died from PE, 24 (43%) stated up to 5, and 1 (2%) reported between 5 and 9 deaths secondary to PE. Fig. 3 shows the distribution of patients who died from PE within 30 days from lung cancer surgery based on surgeons’ beliefs whether or not their patients were on VTE
prophylaxis preoperatively and/or postoperatively. Thirty-day mortality secondary to PE was commonly reported by surgeons who do not use extended VTE prophylaxis after hospital discharge (P ¼ 0.02). Forty-nine (88%) of respondents stated they would change their practice regarding VTE prophylaxis should guidelines with strong recommendations become available. The rest of respondents (12%) stated they would not follow future guidelines regardless of strength of recommendations because despite those documents, they would be the ones dealing with complications secondary to VTE prophylaxis.
DISCUSSION VTE remains a major cause of morbidity, mortality, and economic burden in patients with cancer living in modern societies.9 Routine thromboprophylaxis is recommended for patients with cancer throughout their hospitalization, which should be continued for at least 7e10 days after discharge according to the guidelines published by the American Society of Clinical Oncology (ASCO) and the American College of Chest Physicians.7,8 Extended VTE prophylaxis for up to 30 days after oncologic abdominopelvic surgery is also recommended (Level I B evidence).7 The use of LMWH is recommended over warfarin for VTE treatment in patients with cancer. The use of the new oral anticoagulants, such as direct thrombin or factor Xa inhibitors for VTE prophylaxis, has been advocated in nononcologic patients. However, further research is still needed to recommend the use of these new oral anticoagulants in patients with cancer based on the scarce literature available.7 The lack of data focused on VTE prophylaxis and oncologic lung cancer resections translates into unknown practice patterns, which are likely to be
6 Malgor et al.
Annals of Vascular Surgery
Fig. 2. (A) Rate of DVT over the last two years in patients undergoing oncologic lung resections. (B) Distribution of DVT based on whether or not patients were on VTE prophylaxis.
Fig. 3. Distribution of patients who died from PE within 30 days from lung cancer surgery based on surgeons’ beliefs whether or not their patients were on VTE prophylaxis perioperatively.
guided by personal preferences and data extrapolated from other different medical issues, such as oncologic abdominopelvic resections. Our survey was created to understand how thoracic surgeons use chemical VTE prophylaxis before and after oncologic lung resections. Little is known about perception and adherence to published VTE guidelines by thoracic surgeons. Recently, the Prophylaxis-foR-venOusthroMbOembolism-assessmenT-questionnairE study collaborators administered a questionnaire based on current VTE guidelines to chest physicians.10 This study which included surgeons and other physicians demonstrated that thoracic surgeons are more likely to underprophylax their patients.10 The questionnaire was distributed in Tehran, Iran, to participants of a clinical international summit on lung disease. Unfortunately, distinction of surgeons by location was not provided in the study. It is clear that based on the discrepancy between our results among
thoracic surgeons, geographic location and type of practice and training play a role in the use of VTE thromboprophylaxis. With this in mind, we elected to query thoracic surgeons practicing mainly in North America to gauge their perceptions and adherence to VTE guidelines. The risk of developing VTE attributed to lung cancer (mainly nonesmall cell carcinoma) has been shown to be higher than previously thought.2,3 In a large study based on the California cancer registry, which tracked 91,933 patients with primary lung cancer, the incidence of VTE was found to be 3% and 3.4% at 1 and 3 years following diagnosis.2 However, studies assessing the incidence of VTE in patients undergoing lung cancer resection found it to range between 0.2% and 19%.5 A study of 336 patients who underwent pneumonectomy for malignancy showed overall prognosis of these patients who develop VTE to be poorer compared to surgical patients who did not develop postoperative VTE events.4 In our survey, we found the majority of surgeons are using chemical VTE prophylaxis when they operate on patients with lung cancer preoperatively and postoperatively. An interesting finding of our survey is that the magnitude of the procedure, the surgeons’ experience, and their operative volume appear not to play a critical role in their decision whether or not to use anticoagulants for prophylaxis. Extended VTE prophylaxis up to 30 days, which has been studied and emphasized following oncologic abdominopelvic surgery, was found to be prescribed only by 2 (4%) thoracic surgeons operating on patients with lung cancer. Two (4%) more surgeons reported the use of prophylaxis for up to 11 days after discharge from the hospital as suggested by ASCO when performing any major surgery in patients with cancer in general. The
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reasons for not using extended VTE prophylaxis in this subset of patient are not clear. Excessive risk of bleeding complications directly and indirectly related to surgery (e.g., gastrointestinal bleed), fall risk, cost of anticoagulants, or simply personal preference are potential reasons for not using extended VTE prophylaxis in patient with lung cancer undergoing resection. Further research is clearly necessary to address the efficacy and costeffectiveness of extended 30-day VTE prophylaxis in this subset of patients. A systematic review of the literature performed by Christensen et al.5 demonstrated that major bleeding in patients undergoing oncologic lung resections varies from 0.6% to 4.5%. Chemical VTE prophylaxis was only linked to major bleeding in 1 study.11 In this particular study, the only patient who had an intrathoracic bleed received twice daily 40 mg of enoxaparin which is considered a high prophylactic dose.11 When thoracic surgeons were asked about the risk of bleeding associated with VTE prophylaxis before and after oncologic lung resection and about the likelihood that a reintervention may be necessary to control it in our survey, the majority of them stated chemical VTE prophylaxis was not the culprit of major bleeding. This was corroborated when respondents stated they would not base their future decisions on past episodes of postoperative intrathoracic bleeding. Though, some respondents stated they would hold VTE prophylaxis for 24 hr after an episode of intrathoracic bleeding regardless of its underlying cause based on personal reasons. To date, high-quality data linking VTE prophylaxis to postoperative intrathoracic bleeding, its true incidence, and stratification by complexity of oncologic lung resection is missing. Postoperative mortality secondary to PE in patients undergoing lung resection for malignancy is allegedly low.12 However, it is remarkable that a little less than half of the surgeons answering our survey reported up to 5 deaths clearly related to postoperative PE during their careers in this subset of patients. Some surgeons also reported that their patients were on chemical thromboprophylaxis when the PE occurred. The mean risk of developing VTE in this subset of patients based on observational studies is estimated to be 5.8% regardless of the use of postoperative VTE chemical prophylaxis.5 Hypercoagulability in patients with lung cancer who undergo lung resection was investigated in a randomized clinical trial comparing high- and low-dose heparin prophylaxis.11 The authors concluded that not all of these patients can be considered ‘‘hypercoagulable,’’ but some of them are and will perhaps need more than the standard,
Venous thromboprophylaxis and oncologic chest surgery 7
once daily subcutaneous injection of LMWH in order to prevent an episode of VTE.11 This study has its limitations, such as the use of random morning thromboelastography to determine hypercoagulability. Others have also investigated the potential hypercoagulability intraoperatively and postoperatively despite curative resection of the primary tumor.13e15 This randomized controlled trial along with available literature13e15 and the responses collected in our survey suggests that investigating how VTE prophylaxis should be carried out in this cohort of patient may not be straight forward. Study Limitations All surveys containing outcome questions rely on information based on past respondents’ experience. Therefore, memory biases may occur despite the severity of the adverse outcome investigated such as death. To overcome such bias, a short interval period such as the last 2 years of a surgeon’s practice was utilized to track DVT events but not mortality secondary to PE, which had its frequency assessed over the respondents’ career due to considerably lower rates of PE compared to episodes of DVT. We acknowledge prior episodes of VTE increases the risk of VTE recurrence; however, we did not include in our study a question about it because it would be difficult to quantify such events based solely on the surgeon’s recollections. The number of respondents in our study was below expected for such a timely topic, which likely decreased its statistical power. The reasons for low response rate are fairly unknown. No honorarium was offered to complete this survey. It is likely that paying an honorarium would have increased the response rate; however, it is not possible to ascertain if the numbers of respondents would have increased sufficiently to generate significantly more responses that would have changed the results. The GTSC is a smaller group of thoracic surgeons compared to other societies, such as the Society of Thoracic Surgeons which has a few thousands of active members performing heart, lung, esophageal, and other surgical procedures within the chest. Despite the GTSC smaller size, we elected to inquire its active surgeons because they dedicate at least 50% of their practice to thoracic surgery. We believe the high number of surveys that have been sent over the past years to the GTSC members along with those surgeons’ busy daily practices may have decreased their interest despite the importance of the topic. Nonetheless, the low number of respondents to this pilot survey does provide a sense of how several thoracic surgeons deal with chemical VTE
8 Malgor et al.
prophylaxis in their practices which is important to guide future research and quality initiatives in the topic.
CONCLUSIONS The majority of thoracic surgeons surveyed believe that chemical VTE prophylaxis is safe and should be used regardless of the magnitude of oncologic lung resections. Based on our past experience and despite scarce data on the topic, we believe chemical VTE prophylaxis should be utilized to prevent VTE whenever the intraoperative and postoperative risk of bleeding is considered low. Extended 30-day VTE prophylaxis is not yet used by this survey respondents. The majority of thoracic surgeons expressed great interest to follow future guidelines on VTE prophylaxis for oncologic lung resections shall they become available in the future. In this regard, we believe that the initial step would be to create a national registry or to start a quality initiative program through the Society for Thoracic Surgery in order to gather data on incidence and complications related to VTE prophylaxis in this specific setting. Concomitantly, a randomized study could be performed to address additional questions, such as the efficacy and risks of combined chemical and mechanical versus mechanical VTE prophylaxis alone versus no prophylaxis. A randomized study would also be helpful to further investigate the efficacy and safety of different regimens and types of anticoagulants in this cohort of patients. REFERENCES 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933e8.
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2. Chew HK, Davies AM, Wun T, et al. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost 2008;6:601e8. 3. Tagalakis V, Levi D, Agulnik JS, et al. High risk of deep vein thrombosis in patients with non-small cell lung cancer: a cohort study of 493 patients. J Thorac Oncol 2007;2:729e34. 4. Mason DP, Quader MA, Blackstone EH, et al. Thromboembolism after pneumonectomy for malignancy: an independent marker of poor outcome. J Thorac Cardiovasc Surg 2006;131:711e8. 5. Christensen TD, Vad H, Pedersen S, et al. Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. Ann Thorac Surg 2014;97:394e400. 6. Malgor RD, Bilfinger TV, Labropoulos N. A systematic review of pulmonary embolism in patients with lung cancer. Ann Thorac Surg 2012;94:311e6. 7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315e52. 8. Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654e6. 9. Kourlaba G, Relakis J, Mylonas C, et al. The humanistic and economic burden of venous thromboembolism in cancer patients: a systematic review. Blood Coagul Fibrinolysis 2015;26:13e31. 10. Bikdeli B, Sharif-Kashani B, Raeissi S, et al. Chest physicians’ knowledge of appropriate thromboprophylaxis: insights from the PROMOTE study. Blood Coagul Fibrinolysis 2011;22: 667e72. 11. Attaran S, Somov P, Awad WI. Randomised high- and low-dose heparin prophylaxis in patients undergoing thoracotomy for benign and malignant disease: effect on thrombo-elastography. Eur J Cardiothorac Surg 2010;37:1384e90. 12. Tesselaar ME, Osanto S. Risk of venous thromboembolism in lung cancer. Curr Opin Pulm Med 2007;13:362e7. 13. Thorson CM, Van Haren RM, Ryan ML, et al. Persistence of hypercoagulable state after resection of intra-abdominal malignancies. J Am Coll Surg 2013;216:580e9. discussion 89e90. 14. Thorson CM, Van Haren RM, Ryan ML, et al. Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection. Surgery 2014;155:134e44. 15. Van Haren RM, Valle EJ, Thorson CM, et al. Long-term coagulation changes after resection of thoracoabdominal malignancies. J Am Coll Surg 2014;218:846e54.
Background: Controversies on chemical venous thromboembolic (VTE) prophylaxis in patients undergoing lung resection for malignancy exist. The available guidelines on VTE do not specifically address its prophylaxis in patients undergoing oncologic lung resections. The goal of this survey was to evaluate the perception of VTE prophylaxis among thoracic surgeons performing these operations. Methods: A self-reported online survey was distributed to 267 active members of the General Thoracic Surgical Club between July and September 2015. The survey consisted of 22 questions related to the use of chemical venous thromboprophylaxis in patients undergoing oncologic lung resection and their impact on outcomes. Results: Fifty-six thoracic surgeons replied to the survey. The majority of these surgeons (57%) perform both open and thoracoscopic surgery for lung cancer. All respondents stated that treatment modality and extent of surgical resection have no influence on their decision to use chemical VTE prophylaxis. Twenty-two (39%) respondents do not use chemical VTE prophylaxis prior to their oncologic lung resections, while the remaining 34 (61%) reported use of anticoagulants prior to them. None of the respondents prescribe extended 30-day VTE prophylaxis to these patients. Forty-nine (87%) respondents believe that chemical VTE prophylaxis is not related to major postoperative bleeding episodes. Forty-five (81%) respondents reported that none of their reoperations for bleeding were secondary to VTE prophylaxis or if it was, that isolated event could be successfully managed nonoperatively. Conclusions: The majority of thoracic surgeons surveyed believe that chemical VTE prophylaxis is safe and should be used regardless of the magnitude of oncologic lung resections whenever possible. Extended 30-day VTE prophylaxis is not yet used by the survey respondents.
INTRODUCTION 1
Division of Vascular Surgery, Department of Surgery, The University of Oklahoma, Tulsa, OK. 2 Division of Cardiothoracic Surgery, Department of Surgery, Stony Brook University Medical Center, Stony Brook, NY.
Correspondence to: Rafael D. Malgor, MD, Division of Vascular Surgery, Department of Surgery, The University of Oklahoma, 1919 S. Wheeling Avenue, Suite 600, Tulsa, OK 74133, USA; E-mail: [email protected] Ann Vasc Surg 2017; -: 1–8 http://dx.doi.org/10.1016/j.avsg.2017.03.188 Ó 2017 Elsevier Inc. All rights reserved. Manuscript received: April 7, 2016; manuscript accepted: March 2, 2017; published online: - - -
Venous thromboembolism (VTE) remains an important cause of morbidity and mortality in patients with cancer.1e3 Patients undergoing oncologic lung resection are at high risk of pulmonary embolism (PE) and deep vein thrombosis (DVT).4 Recently, several systematic reviews have emphasized the importance of knowing the incidence of VTE in this cohort of patients and the impact of chemical thromboprophylaxis.5,6 Nonetheless, the use of VTE prophylaxis and its currently used regimens in this subset of patients remains vastly unknown. 1
2 Malgor et al.
Current guidelines recommend that patients undergoing oncologic resection must receive chemical VTE prophylaxis with unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) plus mechanical thromboprophylaxis whenever possible provided the risk of bleeding is not high.7,8 However, these guidelines are mainly based on data from patients with abdominopelvic malignancies. Recommendations on VTE prophylaxis exist for patients undergoing thoracic surgery, but they are not specific for oncologic thoracic patients. In addition, the level of evidence varies widely when it comes to recommending chemical, mechanical, a combination of both, or no prophylaxis for nononcologic patients.7 These recommendations rely on perioperative risk of bleeding which is often difficult to gauge and on VTE risk stratification using validated assessment tools (e.g. Caprini scores), which are not a daily routine in several centers performing thoracic surgery.7 For instance, gauging the risk of bleeding prior to lung resections is cumbersome especially in certain cases when pneumonectomies or en bloc resection for bronchogenic carcinoma with chest wall involvement is performed. Little is known about the adherence and perception of thoracic surgeons of chemical VTE prophylaxis and its complications as well as morbidity and mortality related to VTE in their practices. The purpose of this research is to understand the perception and current practice among thoracic surgeons of chemical VTE prophylaxis when dealing with patients undergoing lung resection for cancer.
METHODS Population Selection and Survey Distribution Members of the General Thoracic Surgical Club (GTSC) were invited to participate in an online survey about chemical VTE prophylaxis in patients undergoing surgery for lung cancer. The GTSC was founded in 1986 and is composed of only boardcertified surgeons by the American Board of Thoracic Surgery whose practice consists of at least 50% of general thoracic surgery. Currently, the GTSC has 267 active members. Approval from the University of Oklahoma institutional review board (Committees on Research Involving Human Subjects) was obtained prior to launching the survey. The electronic contact mail information of GTSC members was never available to the researchers; instead, the GTSC secretariat was responsible to distribute the survey in order to
Annals of Vascular Surgery
prevent identification of respondents. Electronic surveys were created using QualtricsÔ (Qualtrics, Provo, UT), an online ballot tool. All responses were received anonymously. GTSC members who have been retired for more than 10 years were excluded from analysis. This was a voluntary survey, which was distributed initially at the end of July 2015. A welcoming survey email was sent to all GTSC members containing a brief description of project goals along with a hyperlink to access the electronic, web-based survey. All active members of the GTSC were initially emailed, but only 33 responses were recorded after the first attempt. A second email was sent 4 weeks later, the number of respondents then reached 56. The last reminder was sent 8 weeks after the first welcoming survey email, but this last attempt failed to increase the number of respondents. Responses were collected up to the last day of September 2015. Questionnaire Description Twenty-two multiple choices questions were formulated to evaluate preoperative and postoperative use of chemical VTE prophylaxis among thoracic surgeons who often perform oncologic lung resection. The first 6 questions were designed to gather demographic data, type of practice, geographic location, and years in practice. The following 3 questions were formulated to assess type of procedures and overall number of lung resections performed/year. Questions 10e14 emphasize the VTE prophylaxis regimens used by thoracic surgeons and its characteristics, such as preferred anticoagulants and their posology. Questions 15e21 were formulated to investigate morbidity and mortality related to VTE prophylaxis, such as bleeding, DVT, PE, and death rate encountered by surgeons in their practices. The closing question was focused on gathering information about the thoracic surgeons’ receptivity to a specific guideline on VTE prophylaxis and lung surgery shall it becomes available in the near future. Statistical Analysis Descriptive data are reported as proportion of respondents providing a particular survey response. Statistical comparison between proportions was performed when appropriate. Student’s t-test was utilized to compare continuous variables and chi-squared test to compare categorical variables. A value of P < 0.05 was used for determination of statistical significance. The Statistical Package for Social Sciences v.18.0 was utilized for analysis (SPSS Inc., Chicago, IL).
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Table I. Demographics and geographic location of survey respondents’ thoracic practice Variables
Age (years) Under 30 30e39 40e49 50e59 60e69 70 or greater Total Gender Male Female Total Practice location Northeast (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, Vermont, New Jersey, New York, and Pennsylvania) Midwest (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, Ohio, South Dakota, and Wisconsin) South (Delaware, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, Washington D.C., West Virginia, Alabama, Kentucky, Mississippi, Tennessee, Arkansas, Louisiana, Oklahoma, and Texas) West (Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, Wyoming, Alaska, California, Hawaii, Oregon, Washington) Outside the United States Total
RESULTS Response Rate and Demographics The response rate accounted for 21% of the active GTSC members. The majority of respondents reported practices in the Northeast (N ¼ 19, 34%) followed by the Midwest (N ¼ 15, 27%). Three (5%) out of 56 respondents reported practices outside of the United States, 2 in Canada, and 1 in Italy. There was a significant discrepancy between genders with more male respondents than females. Further details of demographic and geographic location of survey respondents’ practice are shown in Table I. Years of Experience, Practice Patterns, and Scope of Practice All respondents but 2 had greater than 6 years of experience in treating lung cancer. Six respondents were not currently practicing by the time they answered this survey; however, they have been retired for less than 10 years. Fifty (89%) surgeons have careers entirely focused on thoracic surgery,
N
%
0 2 17 21 9 7 56
0 4 30 37 16 13 100
51 5 56
91 9 100
19
34
15
27
12
21
7
13
3 56
5 100
3 (5.5%) others practice cardiac and thoracic surgery, and the remaining 3 (5.5%) surgeons have a mixed thoracic, cardiac, and peripheral vascular surgery practice. The majority of surgeons (57%) perform both open and thoracoscopic surgery for lung cancer. All respondents stated that treatment modality and extent of surgical resection have no influence on their decision to administer chemical VTE prophylaxis to their patients with lung cancer (P ¼ NS). Table II depicts thoracic practice patterns, annual case volume of lung resections, and preferred surgical treatment modalities when dealing with patients with lung cancer. Preferences on Preoperative and Postoperative Use of Chemical VTE Prophylaxis Twenty-two (39%) respondents reported that they do not use VTE prophylaxis prior to wedge resections, lobectomies, or pneumonectomies, while the remaining 34 respondents reported use of either UFH (N ¼ 30, 54%) or LMWH (N ¼ 4, 7%) prior to
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Table II. Practice pattern, preferred surgical modality and annual case volume Variables
Practice pattern Academic practice Private practice with an affiliated teaching program Private practice with no resident or fellow interaction Total Preferred surgical treatment modality for lung cancer I am an open surgeon, I never do lung resections for cancer thoracoscopically or robotically I perform both open and thoracoscopic lung cancer resections I predominantly do lung cancer surgery thoracoscopically, rarely open, never robotically I predominantly do lung cancer surgery thoracoscopically or robotically, never open I do pneumonectomies and lobectomies open, but wedge resections thoracoscopically Total Lung resections for lung cancer/year 0e9 10e29 30e49 50e100 >100 Total
any oncologic lung resections. Surgeons who always use chemical VTE prophylaxis stated that the extent of lung resection, such as pneumonectomies, does not play a role in their decision to use VTE prophylaxis. Three quarters of those who prefer to use subcutaneous UFH prior to surgery use 5000 units every 8 hr as a postoperative prophylaxis regimen; the remaining quarter of respondents prefer to use the same amount of UFH, but every 12 hr. All respondents who use UFH also stated that the first postoperative prophylaxis dose is given within 8 hr after surgery, while those who use LMWH wait until the next day to redose it. There was a trend toward using UFH over LMWH based on longer years in practice (P ¼ 0.05). Surgeons were then asked if they would change their strategy regarding postoperative VTE prophylaxis if the procedure had more intraoperative bleeding than expected. Thirteen (23%) surgeons answered they would hold chemical VTE prophylaxis for at least 24 hr postoperatively based on their purely personal preferences which are not based on evidence-based data. When respondents were asked if they prescribe any VTE prophylaxis upon discharge from the hospital based on patients’ VTE risk factors (i.e., lung cancer, surgery, immobility), the majority of surgeons stated that they do not prescribe any chemical VTE prophylaxis after discharging patients
N
%
37 10 9 56
66 18 16 100
2
4
32 12
57 21
5
9
5
9
56
100
1 5 9 25 16 56
2 9 16 45 28 100
from the hospital. VTE prophylaxis practices and patterns after discharge from hospital are depicted in Fig. 1. Complications Related to Chemical VTE Prophylaxis Forty-nine (87%) respondents believe that chemical VTE prophylaxis is safe and it is not related to any additional postoperative bleed their patients have had in the past. Two (4%) respondents believe that chemical VTE prophylaxis has been the cause of a postoperative bleed, which has made them refrain from using it in their major oncologic resections. The remaining 5 (9%) surgeons reported a few postoperative bleeding events they believe have been secondary to the use of prophylactic heparin given preoperatively and/or postoperatively; however, regardless of the impression of increased risk of postoperative bleed related to chemical thromboprophylaxis, these 5 surgeons continue to use it in order to prevent DVT and PE. When asked if a reoperation had to be performed due to postoperative bleed, which was believed to be secondary to administration of chemical VTE prophylaxis, 7 (12%) surgeons reported no correctable surgical causes found during reoperation and another 4 (7%) stated the bleed was secondary to a bleeding vessel. The majority of remaining
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Venous thromboprophylaxis and oncologic chest surgery 5
Fig. 1. Use of chemical thromboprophylaxis after discharge from hospital.
surgeons (81%) reported they either believed that none of their reoperations for bleeding were secondary to VTE prophylaxis or that whenever a postoperative bleed occurred and it was deemed to be related to VTE prophylaxis, that specific event was successfully managed nonoperatively. Incidence of VTE and Its Morbidity and Mortality The respondents were asked if they recalled any episodes of DVT or PE in patients who underwent oncologic lung resection that occurred over the past 2 years. Twenty-three (41%) respondents answered that no episodes of VTE have occurred in this time span. Twenty-six (46%) surgeons recalled at least 1e2 episodes of VTE over the past 2 years, and 7 (13%) reported at least 3e5 cases of VTE in their practice. None of the respondents stated more than 5 episodes of VTE over the past 2 years in practice regardless of an available alternative in the survey stating VTE occurrence greater than 5 episodes. Surgeons were finally questioned about the percentage rate of DVT over the years in their cohort of oncologic patients undergoing lung resection (Fig. 2A) and if they believed that the patients were on VTE prophylaxis when they developed a DVT (Fig. 2B). They were also asked how many of their patients had died from PE within 30 days from an index oncologic lung resection over the past 10 years. Thirty-one (55%) answered none of their patients have ever died from PE, 24 (43%) stated up to 5, and 1 (2%) reported between 5 and 9 deaths secondary to PE. Fig. 3 shows the distribution of patients who died from PE within 30 days from lung cancer surgery based on surgeons’ beliefs whether or not their patients were on VTE
prophylaxis preoperatively and/or postoperatively. Thirty-day mortality secondary to PE was commonly reported by surgeons who do not use extended VTE prophylaxis after hospital discharge (P ¼ 0.02). Forty-nine (88%) of respondents stated they would change their practice regarding VTE prophylaxis should guidelines with strong recommendations become available. The rest of respondents (12%) stated they would not follow future guidelines regardless of strength of recommendations because despite those documents, they would be the ones dealing with complications secondary to VTE prophylaxis.
DISCUSSION VTE remains a major cause of morbidity, mortality, and economic burden in patients with cancer living in modern societies.9 Routine thromboprophylaxis is recommended for patients with cancer throughout their hospitalization, which should be continued for at least 7e10 days after discharge according to the guidelines published by the American Society of Clinical Oncology (ASCO) and the American College of Chest Physicians.7,8 Extended VTE prophylaxis for up to 30 days after oncologic abdominopelvic surgery is also recommended (Level I B evidence).7 The use of LMWH is recommended over warfarin for VTE treatment in patients with cancer. The use of the new oral anticoagulants, such as direct thrombin or factor Xa inhibitors for VTE prophylaxis, has been advocated in nononcologic patients. However, further research is still needed to recommend the use of these new oral anticoagulants in patients with cancer based on the scarce literature available.7 The lack of data focused on VTE prophylaxis and oncologic lung cancer resections translates into unknown practice patterns, which are likely to be
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Fig. 2. (A) Rate of DVT over the last two years in patients undergoing oncologic lung resections. (B) Distribution of DVT based on whether or not patients were on VTE prophylaxis.
Fig. 3. Distribution of patients who died from PE within 30 days from lung cancer surgery based on surgeons’ beliefs whether or not their patients were on VTE prophylaxis perioperatively.
guided by personal preferences and data extrapolated from other different medical issues, such as oncologic abdominopelvic resections. Our survey was created to understand how thoracic surgeons use chemical VTE prophylaxis before and after oncologic lung resections. Little is known about perception and adherence to published VTE guidelines by thoracic surgeons. Recently, the Prophylaxis-foR-venOusthroMbOembolism-assessmenT-questionnairE study collaborators administered a questionnaire based on current VTE guidelines to chest physicians.10 This study which included surgeons and other physicians demonstrated that thoracic surgeons are more likely to underprophylax their patients.10 The questionnaire was distributed in Tehran, Iran, to participants of a clinical international summit on lung disease. Unfortunately, distinction of surgeons by location was not provided in the study. It is clear that based on the discrepancy between our results among
thoracic surgeons, geographic location and type of practice and training play a role in the use of VTE thromboprophylaxis. With this in mind, we elected to query thoracic surgeons practicing mainly in North America to gauge their perceptions and adherence to VTE guidelines. The risk of developing VTE attributed to lung cancer (mainly nonesmall cell carcinoma) has been shown to be higher than previously thought.2,3 In a large study based on the California cancer registry, which tracked 91,933 patients with primary lung cancer, the incidence of VTE was found to be 3% and 3.4% at 1 and 3 years following diagnosis.2 However, studies assessing the incidence of VTE in patients undergoing lung cancer resection found it to range between 0.2% and 19%.5 A study of 336 patients who underwent pneumonectomy for malignancy showed overall prognosis of these patients who develop VTE to be poorer compared to surgical patients who did not develop postoperative VTE events.4 In our survey, we found the majority of surgeons are using chemical VTE prophylaxis when they operate on patients with lung cancer preoperatively and postoperatively. An interesting finding of our survey is that the magnitude of the procedure, the surgeons’ experience, and their operative volume appear not to play a critical role in their decision whether or not to use anticoagulants for prophylaxis. Extended VTE prophylaxis up to 30 days, which has been studied and emphasized following oncologic abdominopelvic surgery, was found to be prescribed only by 2 (4%) thoracic surgeons operating on patients with lung cancer. Two (4%) more surgeons reported the use of prophylaxis for up to 11 days after discharge from the hospital as suggested by ASCO when performing any major surgery in patients with cancer in general. The
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reasons for not using extended VTE prophylaxis in this subset of patient are not clear. Excessive risk of bleeding complications directly and indirectly related to surgery (e.g., gastrointestinal bleed), fall risk, cost of anticoagulants, or simply personal preference are potential reasons for not using extended VTE prophylaxis in patient with lung cancer undergoing resection. Further research is clearly necessary to address the efficacy and costeffectiveness of extended 30-day VTE prophylaxis in this subset of patients. A systematic review of the literature performed by Christensen et al.5 demonstrated that major bleeding in patients undergoing oncologic lung resections varies from 0.6% to 4.5%. Chemical VTE prophylaxis was only linked to major bleeding in 1 study.11 In this particular study, the only patient who had an intrathoracic bleed received twice daily 40 mg of enoxaparin which is considered a high prophylactic dose.11 When thoracic surgeons were asked about the risk of bleeding associated with VTE prophylaxis before and after oncologic lung resection and about the likelihood that a reintervention may be necessary to control it in our survey, the majority of them stated chemical VTE prophylaxis was not the culprit of major bleeding. This was corroborated when respondents stated they would not base their future decisions on past episodes of postoperative intrathoracic bleeding. Though, some respondents stated they would hold VTE prophylaxis for 24 hr after an episode of intrathoracic bleeding regardless of its underlying cause based on personal reasons. To date, high-quality data linking VTE prophylaxis to postoperative intrathoracic bleeding, its true incidence, and stratification by complexity of oncologic lung resection is missing. Postoperative mortality secondary to PE in patients undergoing lung resection for malignancy is allegedly low.12 However, it is remarkable that a little less than half of the surgeons answering our survey reported up to 5 deaths clearly related to postoperative PE during their careers in this subset of patients. Some surgeons also reported that their patients were on chemical thromboprophylaxis when the PE occurred. The mean risk of developing VTE in this subset of patients based on observational studies is estimated to be 5.8% regardless of the use of postoperative VTE chemical prophylaxis.5 Hypercoagulability in patients with lung cancer who undergo lung resection was investigated in a randomized clinical trial comparing high- and low-dose heparin prophylaxis.11 The authors concluded that not all of these patients can be considered ‘‘hypercoagulable,’’ but some of them are and will perhaps need more than the standard,
Venous thromboprophylaxis and oncologic chest surgery 7
once daily subcutaneous injection of LMWH in order to prevent an episode of VTE.11 This study has its limitations, such as the use of random morning thromboelastography to determine hypercoagulability. Others have also investigated the potential hypercoagulability intraoperatively and postoperatively despite curative resection of the primary tumor.13e15 This randomized controlled trial along with available literature13e15 and the responses collected in our survey suggests that investigating how VTE prophylaxis should be carried out in this cohort of patient may not be straight forward. Study Limitations All surveys containing outcome questions rely on information based on past respondents’ experience. Therefore, memory biases may occur despite the severity of the adverse outcome investigated such as death. To overcome such bias, a short interval period such as the last 2 years of a surgeon’s practice was utilized to track DVT events but not mortality secondary to PE, which had its frequency assessed over the respondents’ career due to considerably lower rates of PE compared to episodes of DVT. We acknowledge prior episodes of VTE increases the risk of VTE recurrence; however, we did not include in our study a question about it because it would be difficult to quantify such events based solely on the surgeon’s recollections. The number of respondents in our study was below expected for such a timely topic, which likely decreased its statistical power. The reasons for low response rate are fairly unknown. No honorarium was offered to complete this survey. It is likely that paying an honorarium would have increased the response rate; however, it is not possible to ascertain if the numbers of respondents would have increased sufficiently to generate significantly more responses that would have changed the results. The GTSC is a smaller group of thoracic surgeons compared to other societies, such as the Society of Thoracic Surgeons which has a few thousands of active members performing heart, lung, esophageal, and other surgical procedures within the chest. Despite the GTSC smaller size, we elected to inquire its active surgeons because they dedicate at least 50% of their practice to thoracic surgery. We believe the high number of surveys that have been sent over the past years to the GTSC members along with those surgeons’ busy daily practices may have decreased their interest despite the importance of the topic. Nonetheless, the low number of respondents to this pilot survey does provide a sense of how several thoracic surgeons deal with chemical VTE
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prophylaxis in their practices which is important to guide future research and quality initiatives in the topic.
CONCLUSIONS The majority of thoracic surgeons surveyed believe that chemical VTE prophylaxis is safe and should be used regardless of the magnitude of oncologic lung resections. Based on our past experience and despite scarce data on the topic, we believe chemical VTE prophylaxis should be utilized to prevent VTE whenever the intraoperative and postoperative risk of bleeding is considered low. Extended 30-day VTE prophylaxis is not yet used by this survey respondents. The majority of thoracic surgeons expressed great interest to follow future guidelines on VTE prophylaxis for oncologic lung resections shall they become available in the future. In this regard, we believe that the initial step would be to create a national registry or to start a quality initiative program through the Society for Thoracic Surgery in order to gather data on incidence and complications related to VTE prophylaxis in this specific setting. Concomitantly, a randomized study could be performed to address additional questions, such as the efficacy and risks of combined chemical and mechanical versus mechanical VTE prophylaxis alone versus no prophylaxis. A randomized study would also be helpful to further investigate the efficacy and safety of different regimens and types of anticoagulants in this cohort of patients. REFERENCES 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933e8.
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2. Chew HK, Davies AM, Wun T, et al. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost 2008;6:601e8. 3. Tagalakis V, Levi D, Agulnik JS, et al. High risk of deep vein thrombosis in patients with non-small cell lung cancer: a cohort study of 493 patients. J Thorac Oncol 2007;2:729e34. 4. Mason DP, Quader MA, Blackstone EH, et al. Thromboembolism after pneumonectomy for malignancy: an independent marker of poor outcome. J Thorac Cardiovasc Surg 2006;131:711e8. 5. Christensen TD, Vad H, Pedersen S, et al. Venous thromboembolism in patients undergoing operations for lung cancer: a systematic review. Ann Thorac Surg 2014;97:394e400. 6. Malgor RD, Bilfinger TV, Labropoulos N. A systematic review of pulmonary embolism in patients with lung cancer. Ann Thorac Surg 2012;94:311e6. 7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315e52. 8. Lyman GH, Bohlke K, Khorana AA, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update 2014. J Clin Oncol 2015;33:654e6. 9. Kourlaba G, Relakis J, Mylonas C, et al. The humanistic and economic burden of venous thromboembolism in cancer patients: a systematic review. Blood Coagul Fibrinolysis 2015;26:13e31. 10. Bikdeli B, Sharif-Kashani B, Raeissi S, et al. Chest physicians’ knowledge of appropriate thromboprophylaxis: insights from the PROMOTE study. Blood Coagul Fibrinolysis 2011;22: 667e72. 11. Attaran S, Somov P, Awad WI. Randomised high- and low-dose heparin prophylaxis in patients undergoing thoracotomy for benign and malignant disease: effect on thrombo-elastography. Eur J Cardiothorac Surg 2010;37:1384e90. 12. Tesselaar ME, Osanto S. Risk of venous thromboembolism in lung cancer. Curr Opin Pulm Med 2007;13:362e7. 13. Thorson CM, Van Haren RM, Ryan ML, et al. Persistence of hypercoagulable state after resection of intra-abdominal malignancies. J Am Coll Surg 2013;216:580e9. discussion 89e90. 14. Thorson CM, Van Haren RM, Ryan ML, et al. Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection. Surgery 2014;155:134e44. 15. Van Haren RM, Valle EJ, Thorson CM, et al. Long-term coagulation changes after resection of thoracoabdominal malignancies. J Am Coll Surg 2014;218:846e54.