Is asymptomatic postoperative venous thromboembolism associated with long-term survival in patients undergoing lung resection for malignancy?

Central MessageThis study highlights that with regular venous thromboembolism (VTE) screening and subsequent treatment, postoperative thrombotic events may not impact the long-term survival of lung cancer patients.See Commentaries on pages 246 and 248. This study highlights that with regular venous thromboembolism (VTE) screening and subsequent treatment, postoperative thrombotic events may not impact the long-term survival of lung cancer patients. See Commentaries on pages 246 and 248. Venous thromboembolism (VTE), including deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a significant cause of morbidity and mortality after lung resection.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Previous studies have found postoperative VTEs are associated with increased 30-day mortality.2Thomas D.C. Arnold B.N. Hoag J.R. Salazar M.C. Detterbeck F.C. Boffa D.J. et al.Timing and risk factors associated with venous thromboembolism after lung cancer resection.Ann Thorac Surg. 2018; 105: 1469-1475Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Although the majority of patients with lung cancer receive in-hospital prophylaxis,3Kearon C. Akl E.A. Ornelas J. Blaivas A. Jimenez D. Bounameaux H. et al.Antithrombotic therapy for VTE disease.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3088) Google Scholar the American College of Surgeons National Surgical Quality Improvement Program reports that 44% of VTEs after lung resection occur after hospital discharge.2Thomas D.C. Arnold B.N. Hoag J.R. Salazar M.C. Detterbeck F.C. Boffa D.J. et al.Timing and risk factors associated with venous thromboembolism after lung cancer resection.Ann Thorac Surg. 2018; 105: 1469-1475Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Although general surgical oncology and orthopedic surgery have developed recommendations for extended, postdischarge prophylaxis,4Lyman G.H. Bohlke K. Khorana A.A. Kuderer N.M. Lee A.Y. Arcelus J.I. 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: 654-656Crossref PubMed Scopus (582) Google Scholar no such guidelines exist for lung cancer surgery. Furthermore, evidence suggests that VTE development after curative oncologic resections portends worse overall survival beyond the immediate postoperative period, potentially indicating a more aggressive malignancy.5Auer R.A.C. Scheer A.S. McSparron J.I. Schulman A.R. Tuorto S. Doucette S. et al.Postoperative venous thromboembolism predicts survival in cancer patients.Ann Surg. 2012; 255: 963-970Crossref PubMed Scopus (28) Google Scholar Our group previously conducted a prospective cohort study across 2 tertiary hospitals in the Canadian province of Ontario and found a 12% incidence of screening-detected postoperative VTEs, all diagnosed post-discharge.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar In light of evidence suggesting VTEs are associated with poor oncologic outcomes, we conducted a follow-up analysis to examine the relationship between postoperative VTEs and long-term survival. The original study recruited patients undergoing lung cancer resection across 2 tertiary centers in Ontario.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Patients older than the age of 18 years undergoing lung resection were included. All patients received in-hospital pharmacologic and mechanical prophylaxis, including graduated compression stockings and chemical prophylaxis with daily subcutaneous low-molecular weight heparin, or twice-daily unfractionated heparin. All study patients underwent screening computed tomography pulmonary angiography and bilateral above-knee lower-limb venous Doppler ultrasonography at 30 days postoperatively. Screening of asymptomatic patients was conducted only for study patients and is not standard of care. Patients with previous thrombotic events or on therapeutic anticoagulation were excluded.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar For the present study, patients were examined with a median follow-up of 3.6 years after surgery. Patients with postoperative VTEs were compared with those without VTE. We used a proportional hazard Cox regression to compare survival between the groups. Age, sex, smoking status, and comorbidities were included in the univariate analysis. Variables that achieved significance were then included in the multivariable regression. Outcomes of interest were cancer recurrence and overall survival. Importantly, 22% of patients underwent pulmonary metastatectomy with a non-lung primary malignancy. Given the small number of total patients, all patients were included in the final survival curve. The patients provided informed consent for the publication of the study data. The original analysis included 157 patients; 12% (n = 19) developed a postoperative VTE. One death from massive PE resulted in a 5% 30-day mortality rate from VTE in the VTE group, whereas none of the non-VTE group died.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Only 4 patients (21.1%) were symptomatic.1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Univariate analysis showed no difference between patients with and without a VTE with regards to baseline characteristics (Table 1).1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google ScholarTable 1Baseline characteristics of the original cohort (N = 157)1Agzarian J. Hanna W.C. Schneider L. Schieman C. Finley C.J. Peysakhovich Y. et al.Postdischarge venous thromboembolic complications following pulmonary oncologic resection: an underdetected problem.J Thorac Cardiovasc Surg. 2016; 151: 992-999Abstract Full Text Full Text PDF PubMed Scopus (30) Google ScholarNo postoperative VTE (n = 138)∗Values represent n (%), mean ± standard deviation, or median (range) unless otherwise specified.Postoperative VTE (n = 19)Total†Total for all variables may not add up to 157 due to missing data. (N = 157)P valueAge, y66.25 ± 8.8869.05 ± 11.5166.55 ± 9.24.216Sex (male)62 (44.92)10 (52.63)72 (45.86).626%Predicted FEV172.34 (32.68)82.50 (35.11)73.51 (33.02).220%Predicted DLCO72.07 (19.88)67.0 (14.13)71.48 (19.33).326Charlson Comorbidity Index2.19 ± 2.072.42 ± 2.242.22 ± 2.08.649Length of stay, d6 (3-24)5 (1-5)5 (1-24).185Caprini score 3-427 (19.56)2 (10.52)29 (18.47).441 5+111 (80.43)17 (89.47)128 (81.52)Smoking status Never smoker26 (83.9)5 (16.1)31 (19.7).441 Former smoker79 (90.8)8 (9.2)87 (55.4) Current smoker32 (84.2)6 (15.8)38 (24.2)Tumor pathology T1a27 (81.8)6 (18.2)33 (26.0) T1b18 (85.7)3 (14.3)21 (16.5) T2a35 (83.3)7 (16.7)42 (33.1).513 T2b11 (91.7)1 (8.3)12 (9.4) T316 (100)0.016 (12.6) T43 (100)0.03 (2.4)Lymph node pathology NX4 (100)0.04 (3.1) N079 (85.9)13 (14.1)92 (72.4).566 N121 (91.3)2 (8.7)23 (18.1) N26 (0.8)2 (0.2)8 (6.3)Pathologic stage (TMN) IA37 (26.81)7 (36.84)44 (28.03) IB31 (22.46)6 (31.58)37 (23.57) IIA14 (10.14)1 (5.26)15 (9.55)–‡Due to small sample size, P value is not reliable. IIB7 (5.07)1 (5.26)8 (5.10) IIIA16 (11.59)2 (10.53)18 (11.46) IIIB4 (2.90)0 (0)4 (2.55) Lung metastases21 (15.22)2 (10.53)23 (14.65)Histology Squamous cell29 (21.01)4 (21.05)33 (21.01).827 Adenocarcinoma63 (45.65)10 (52.63)73 (46.50) Other45 (32.61)5 (26.32)50 (31.85)Resection Pneumonectomy6 (4.35)0 (0)6 (3.82) Bilobectomy2 (1.45)0 (0)2 (1.27)–‡Due to small sample size, P value is not reliable. Lobectomy87 (63.04)15 (78.96)102 (64.97) Sublobar43 (31.16)4 (21.05)47 (29.93)Surgical approach VATS76 (55.07)9 (47.37)85 (54.14) Thoracotomy56 (40.58)10 (52.63)66 (42.04).452 Robotic6 (4.35)0 (0)6 (3.82)Groups were compared using t tests and χ2 tests as appropriate. VTE, Venous thromboembolism; FEV1, forced expiratory volume in 1 s; DLCO, diffusion capacity of the lungs for carbon monoxide; VATS, video-assisted thoracoscopic surgery.∗ Values represent n (%), mean ± standard deviation, or median (range) unless otherwise specified.† Total for all variables may not add up to 157 due to missing data.‡ Due to small sample size, P value is not reliable. Open table in a new tab Groups were compared using t tests and χ2 tests as appropriate. VTE, Venous thromboembolism; FEV1, forced expiratory volume in 1 s; DLCO, diffusion capacity of the lungs for carbon monoxide; VATS, video-assisted thoracoscopic surgery. Long-term follow-up was complete for all patients and showed no difference in cancer recurrence between patients with and without a VTE (35% and 32%, respectively, P = 1.000; median follow-up 3.6 years). Results were unchanged when DVT and PE were analyzed separately. There was no difference in overall or disease-specific survival between the 2 groups (Tables 2 and 3, Figure 1). This effect persisted after stratification by disease stage and patient characteristics.Table 2Survival rate (%) over time for patients with and without a postoperative screen−detected VTETime (years since surgery)Number at riskSurvival rate (%)95% confidence intervalNo VTE 0138100NA 112794.989.5-97.5 211486.779.6-91.4 310382.074.4-87.6 41276.367.2-83.1VTE 019100NA 11894.768.1-99.2 21684.258.7-94.6 31380.053.2-91.5 4253.417.6-80.2VTE, Venous thromboembolism; NA, not available. Open table in a new tab Table 3Proportional hazard Cox regression analysis of survival for all patients (VTE + no VTE)nUnivariable HR (95% CI)P valueMultivariable HR (95% CI)P valueAge, y1571.02 (0.98-1.06).239−−Sex.720−− Female72Reference Male851.12 (0.60-2.08)Smoking history.832−− No127Reference Yes301.09 (0.50-2.36)Any VTE.501−− No138Reference Yes191.34 (0.56-3.21)Pathologic stage1491.18 (1.05-1.32).0041.17 (1.05-1.31).005Histology.336−− Squamous cell33Reference− Adenocarcinoma730.92 (0.40-2.16).858 Carcinoid120.00.974 Metastatic231.87 (0.74-4.76).184 Mixed151.90 (0.66-5.47).235Surgery.742−− Pneumonectomy6Reference− Lobectomy1040.60 (0.14-2.56).495 Segmentectomy270.82 (0.17-3.80).798 Wedge200.50 (0.10-2.73).424FEV11490.99 (0.98-1.01).362−−DLCO1460.98 (0.96-1.00).125−−VATS.036NSNS No71Reference Yes840.51 (0.27-0.95)CVA.446−− No152Reference Yes51.74 (0.42-7.21)PVD.076NSNS No148Reference Yes92.34 (0.91-5.98)CAD.951−− No137Reference Yes200.97 (0.38-2.48)Diabetes.066NSNS No134Reference Yes230.26 (0.06-1.09)Obesity.724−− No137Reference Yes201.17 (0.49-2.80)CKD.484−− No134Reference Yes221.34 (0.60-3.02)HR, Hazard ratio; CI, confidence interval; VTE, venous thromboembolism; FEV1, forced expiratory volume in 1 s; DLCO, diffusion capacity of the lungs for carbon monoxide; VATS, video-assisted thoracoscopic surgery; CVA, cerebrovascular accident; PVD, peripheral vascular disease; CAD, coronary artery disease; NS, not significant; CKD, chronic kidney disease. Open table in a new tab VTE, Venous thromboembolism; NA, not available. HR, Hazard ratio; CI, confidence interval; VTE, venous thromboembolism; FEV1, forced expiratory volume in 1 s; DLCO, diffusion capacity of the lungs for carbon monoxide; VATS, video-assisted thoracoscopic surgery; CVA, cerebrovascular accident; PVD, peripheral vascular disease; CAD, coronary artery disease; NS, not significant; CKD, chronic kidney disease. This study found no difference in the long-term survival of patients with lung cancer based on postoperative VTE development. These results stand in contrast to previous evidence suggesting worse overall survival in patients with a postoperative VTE.5Auer R.A.C. Scheer A.S. McSparron J.I. Schulman A.R. Tuorto S. Doucette S. et al.Postoperative venous thromboembolism predicts survival in cancer patients.Ann Surg. 2012; 255: 963-970Crossref PubMed Scopus (28) Google Scholar Notably, this study captured asymptomatic, screening-detected VTEs, prompting treatment of patients who may have not manifested clinical evidence of DVT/PE and remained untreated. It is possible that our findings are due to early identification and subsequent treatment of patients with subclinical VTEs, preventing long-term morbidity from undetected DVT/PEs. The strengths of this study include long-term and granular follow-up of patients post-lung resection. The small sample size is the major limitation, as it increases the likelihood of type II errors. Furthermore, the inclusion of pulmonary metastases in the survival curve decreases the generalizability of results to patients with lung cancer. Finally, bleeding complications after the initiation of therapeutic anticoagulation in the VTE group were not tracked. In conclusion, the present study found that with regular VTE screening and treatment when an event is detected, postoperative VTEs may not impact the long-term survival of patients undergoing lung resection for malignancy. Rather, the morbidity and mortality of postoperative VTEs seems to lie in the short-term postoperative period. To reduce the impact of VTEs on long-term survival, screening for high-risk patients may be warranted to promote early diagnosis and treatment, as treated events are unlikely to impact long-term outcomes. Similar to surgical oncology, thoracic surgeons may consider extended postdischarge VTE prophylaxis for selected patient populations to prevent the development of thrombotic complications.

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