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Should all patients receive extended thromboprophylaxis after resection of primary lung cancer?

Open AccessPublished:July 04, 2022DOI:https://doi.org/10.1016/j.jtcvs.2022.06.016

      Abstract

      Objective

      The optimal duration of thromboprophylaxis in patients undergoing resection of primary lung cancer is not known. We investigated the incidence of pulmonary emboli and venous thromboembolism in patients undergoing early-stage lung cancer resection and the impact of change from short duration to extended thromboprophylaxis.

      Methods

      We reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer following a change in protocol from inpatient-only to extended thromboprophylaxis to 28 days. Propensity-score matching of control (routine inpatient pharmacologic thromboprophylaxis) and treatment group (extended pharmacologic thromboprophylaxis) was performed. Adjustment for covariates based on the Caprini risk assessment model was undertaken. Thromboembolic outcomes were compared between the 2 groups.

      Results

      Seven hundred fifty consecutive patients underwent resection of primary lung cancer at Oxford University Hospitals NHS Foundation Trust between January 2013 and December 2018. Six hundred patients were included for analysis and propensity-score matching resulted in 253 matched pairs. Extended prophylaxis was associated with a significant reduction in pulmonary emboli (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01). One patient (0.4%) developed a bleeding complication within the treatment cohort. Multivariable logistic regression model demonstrated that extended thromboprophylaxis was independently associated with a reduction in postoperative pulmonary emboli.

      Conclusions

      Patients undergoing lung cancer resection surgery are at moderate-to-high risk of postoperative thromboembolic disease. Extended dalteparin for 28 days is safe and is associated with reduced incidence of pulmonary embolus in patients undergoing resection of early-stage primary lung cancer.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      CI (confidence interval), CT (computed tomography), DVT (deep-vein thrombosis), IU (international units), LMWH (low molecular weight heparin), LRTI (lower respiratory tract infection), OR (odds ratio), PE (pulmonary embolism), RAM (risk assessment model), SMD (standardized mean difference), VTE (venous thromboembolism/thromboembolic)
      Figure thumbnail fx2
      Extended thromboprophylaxis was associated with reduced incidence of postoperative PE.
      A change from inpatient only to extended pharmacologic thromboprophylaxis was associated with reduced incidence of pulmonary emboli in patients undergoing resection of primary lung cancer.
      Patients undergoing lung cancer resection surgery are at high risk of postoperative venous thromboembolism. The role and optimal duration of extended thromboprophylaxis in patients undergoing thoracic surgery remain uncertain. We demonstrated that extended thromboprophylaxis with 28 days of dalteparin is safe and is associated with reduced incidence of postoperative pulmonary emboli.
      See Commentary on page 1612.
      Patients undergoing lung cancer resection surgery are at increased risk of postoperative venous thromboembolic (VTE) events, with a reported incidence ranging from 1.6% to 17.9%, and the majority of these events occur after hospital discharge.
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      Timing and risk factors associated with venous thromboembolism after lung cancer resection.
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      Routine venous thromboembolism screening after pneumonectomy: the more you look, the more you see.
      VTE following lung cancer resection is associated with early morbidity and mortality and reduced survival at a year.
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      Routine venous thromboembolism screening after pneumonectomy: the more you look, the more you see.
      This may be related to hypercoagulability secondary to overexpression of tissue factor by malignant cells but may also be influenced by other risk factors, including prolonged operative time, older age, obesity, and pneumonectomy.
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      Timing and risk factors associated with venous thromboembolism after lung cancer resection.
      ,
      • Tesselaar M.E.T.
      • Osanto S.
      Risk of venous thromboembolism in lung cancer.
      Currently, most VTE prevention guidelines recommend routine inpatient prophylactic low molecular weight heparin (LMWH) in thoracic surgery patients at moderate-to-high VTE risk, with some guidelines recommending consideration of pharmacologic VTE prophylaxis for 7 days within the postoperative period.
      National Institute for Health and Care Excellence
      Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE.
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      • et al.
      Prevention of VTE in nonorthopedic surgical patients. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      In major abdominal or pelvic oncological surgery, the role of extended pharmacologic thromboprophylaxis is well-established in reducing the incidence of postoperative VTE compared with shorter regimens.
      • Felder S.
      • Rasmussen M.S.
      • King R.
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      • et al.
      Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery.
      The National Institute for Health and Care Excellence, American Society of Clinical Oncology, and American College of Chest Physicians currently recommend the use of extended prophylaxis with LMWH for up to 4 weeks in these patients.
      National Institute for Health and Care Excellence
      Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE.
      • Key N.S.
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      • Kuderer N.M.
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      • Lee A.Y.Y.
      • Arcelus J.I.
      • et al.
      Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update.
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      • Arcelus J.I.
      • Heit J.A.
      • et al.
      Prevention of VTE in nonorthopedic surgical patients. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      By contrast, the role of extended thromboprophylaxis in patients undergoing thoracic surgery remains uncertain. A tailored approach of pharmacologic VTE prophylaxis via a VTE risk assessment model (RAM), the Caprini RAM, showed a nonsignificant downward trend in VTE events in patients who received extended pharmacologic thromboprophylaxis, suggesting a potential role for extended VTE prophylaxis in a thoracic surgery patient cohort.
      • Sterbling H.M.
      • Rosen A.K.
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      • Hewes P.D.
      • Rao S.R.
      • et al.
      Caprini Risk model decreases venous thromboembolism rates in thoracic surgery cancer patients.
      ,
      • Hachey K.J.
      • Sterbling H.
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      • Pinjic E.
      • Hewes P.D.
      • Munoz J.
      • et al.
      Prevention of postoperative venous thromboembolism in thoracic surgical patients: implementation and evaluation of a Caprini risk assessment protocol.
      We evaluated the incidence of PE and VTE in patients undergoing lung cancer resection and investigated the safety and efficacy of extended pharmacologic thromboprophylaxis in these patients.

      Methods

      Study Design and Patient Characteristics

      We retrospectively reviewed the outcomes of consecutive patients who underwent resection of early-stage primary lung cancer at Oxford University Hospitals NHS Foundation Trust, United Kingdom, between January 2013 and December 2018 to evaluate the incidence of PE (primary outcome) and VTE (secondary outcome). In July 2016, a change in protocol from inpatient only to postoperative extended VTE prophylaxis with 28 days of dalteparin was instituted within our thoracic surgery department.
      Patients were analyzed according to whether they received inpatient only (control group) or extended pharmacological thromboprophylaxis (treatment group). Our routine inpatient care included an Enhanced Recovery After Surgery protocol where patients were admitted on the day of surgery. A VTE risk assessment was undertaken on admission and subcutaneous prophylactic weight-adjusted dose of dalteparin administered, in accordance with hospital guidelines, providing there were no contraindications.
      • Batchelor T.J.P.
      • Rasburn N.J.
      • Abdelnour-Berchtold E.
      • Brunelli A.
      • Cerfolio R.J.
      • Gonzalez M.
      • et al.
      Guidelines for enhanced recovery after lung surgery: recommendations of the enhanced recovery after surgery (ERAS®) Society and the European Society of Thoracic Surgeons (ESTS).
      First dose of inpatient thromboprophylaxis was administered in all patients on the evening after their operation. The majority of patients (those weighing between 40 and 120 kg) received 5000 international units (IU) once daily. In patients weighing between 120 and 150 kg, 7500 IU was administered and in those weighing more than 150 kg, 5000 IU twice daily was indicated. All patients donned Thrombo-Embolus Deterrent stockings as mechanical thromboprophylaxis in both preoperative and postoperative settings unless contraindicated; contraindications included skin disease, peripheral vascular disease, or in the absence of appropriate sizing. In addition, patients received intraoperative intermittent pneumatic compression device application.
      In the treatment group, dalteparin administration was continued beyond hospital discharge to a total of 28 days from the date of surgery. Before discharge, education on subcutaneous administration of dalteparin was provided to patients by nursing staff or hospital pharmacist. Patients with a prolonged hospital admission exceeding the 28-day prophylaxis period had routine thromboprophylaxis until discharge and were included in the treatment group. Patients who returned to the operating theater for bleeding and patients with previous history of VTE or hypercoagulable conditions were included in the protocol.
      Patient demographics and baseline characteristics, including medical comorbidities, smoking history, body mass index, histopathology report, and World Health Organization performance status were included for analysis. Lung cancer was staged using the American Joint Committee on Cancer 8th edition lung cancer staging.
      • Detterbeck F.C.
      • Boffa D.J.
      • Kim A.W.
      • Tanoue L.T.
      The eighth edition lung cancer stage classification.
      Type of surgery was designated as sublobar resection, lobectomy, bilobectomy, extended resection, or pneumonectomy. Surgical approach was video-assisted thoracoscopic surgery or open thoracotomy. Postoperative hemorrhagic complications were recorded and classified according to the Clavien–Dindo grading of surgical complications via review of medical records and electronic patient records.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Caprini RAM scores were retrospectively calculated to assess the risk of VTE. In all patients, duration of surgery exceeded 45 minutes and all patients had lung malignancy. Patients were considered low risk if their Caprini score was <4, moderate risk if score was 5 to 8, and high risk if score was 9 or greater.
      • Pannucci C.J.
      • Swistun L.
      • MacDonald J.K.
      • Henke P.K.
      • Brooke B.S.
      Individualized venous thromboembolism risk stratification using the 2005 caprini score to identify the benefits and harms of chemoprophylaxis in surgical patients: a meta-analysis.
      Lower respiratory tract infections (LRTIs) were defined as postoperative evidence of clinical, biochemical, or radiologic changes consistent with LRTI which warranted treatment with antibiotics.
      Patients with a bleeding disorder, patients established on long-term anticoagulation with either a direct oral anticoagulant or warfarin before the operation, and patients commenced on chronic anticoagulation postoperatively were excluded from our extended thromboprophylaxis protocol. Patients who died from non–VTE-related causes within 6 months of the postoperative period and patients lost to follow-up were excluded from analysis.

      Diagnosis of VTE

      Diagnosis of VTE, which included both deep vein thrombosis (DVT) and pulmonary embolism (PE), was made on either ultrasound Doppler, computed tomography (CT) pulmonary angiogram performed due to clinical suspicion of PE or follow-up contrast-enhanced CT (chest, abdomen, and pelvis) or CT of the chest at 6 months after surgery as part of our institutional CT follow-up program.
      • Mitchell J.
      • Benamore R.
      • Gleeson F.
      • Belcher E.
      Computed tomography follow-up identifies radically treatable new primaries after resection for lung cancer.
      To account for logistics of patients and institutional factors on the organization of scans, we analyzed patient scans for up to 9 months postoperatively. Patients who underwent imaging before 28 days due to clinical suspicion of VTE and were found to be VTE negative had results of their repeat imaging after 28 days and up to 9 months reviewed to confirm there was no VTE incidence following the extended period of thromboprophylaxis.
      A diagnosis of DVT included acute thrombosis of lower-extremity veins (iliac, femoral, popliteal or calf veins) or upper-extremity veins (axillary, subclavian, brachial or internal jugular veins) and PE was defined as acute thrombosis within the pulmonary vasculature. All detected VTE events were symptomatic unless stated otherwise. When the site of thrombosis correlated with the surgical site, a diagnosis of in situ thrombus was made on a balance of probability by a consultant chest radiologist, based on anatomical location in relation to the site of resection, particularly if the area in question represented an isolated filling defect. Where diagnostic doubt remained and the patient was clinically unwell, CT pulmonary angiogram was performed. In situ thrombi were not considered as VTE events and hence were not treated with anticoagulation. Death from VTE was defined as mortality within 10 days of diagnosis of symptomatic VTE event with no alternative attributable primary cause of death.

      Statistical Analysis

      Data analysis was undertaken using R statistical software, version 4.0.3 (R Foundation for Statistical Computing).
      • R Core Team
      R: a language and environment for statistical computing. Vienna: R Foundation for Statistcal Computing.
      Continuous variables were tested for normality using the Kolmogorov–Smirnov test and expressed as either mean ± standard deviation or median ± interquartile range. Categorical variables were expressed as frequencies and relative percentages.
      Propensity-score matching of the control and treatment group was performed by using a logistic regression propensity score. Covariates were determined based on the individual risk factors laid out in the Caprini RAM. One-to-one matching without replacement was performed using nearest-neighbor strategy with caliper width equal to 0.2 sigma.
      • Austin P.C.
      An introduction to propensity score methods for reducing the effects of confounding in observational studies.
      A standardized mean difference (SMD) of <10% between the covariates was deemed to be sufficiently balanced. Sensitivity analysis for unmeasured confounding was performed by calculating the E-value.
      • VanderWeele T.J.
      • Ding P.
      Sensitivity analysis in observational research: introducing the E-value.
      Comparative analysis between the 2 groups was performed using the Fisher exact test and χ2 test for categorical variables and Mann–Whitney U test for nonparametric continuous data. Statistical analysis was performed before and after matching. In the matched cohort, we performed a univariable and multivariable logistic regression model using a stepwise approach to evaluate the association of extended thromboprophylaxis with VTE incidence adjusted for each Caprini risk factor. The Hosmer–Lemeshow statistic was used to measure goodness of fit. Cumulative incidence curves of PE and VTE between the 2 matched groups were plotted and compared using the log-rank test.
      As our study was an evaluation of our standard of care, ethical approval is not required in our Institution. The study was approved by the audit office of Oxford University Hospitals NHS Foundation Trust, United Kingdom.

      Results

      Between January 2013 and December 2018, 750 consecutive patients with primary lung cancer underwent resection. In total, 150 patients were excluded from analysis, resulting in 600 patients for analysis, 297 in the control group and 303 in the treatment group (Figure 1). Patient characteristics and demographics are shown in Table 1. Propensity-matched cohorts consisted of 253 patients in each group. Good balance with SMD <10% across matched covariates was achieved, with the exception of surgical access and acute kidney injury (Table 1).
      Figure thumbnail gr1
      Figure 1Flow diagram of the patient population. CT, Computed tomography.
      Table 1Summary of patient demographics, baseline characteristics, and postoperative variables before and after propensity score matching
      VariablesAll patients (n = 600)UnmatchedSMD (%)MatchedSMD (%)
      Control group (n = 297)Treatment group (n = 303)Control group (n = 253)Treatment group (n = 253)
      Age, y, mean ± SD69 ± 969 ± 969 ± 102.069 ± 969 ± 102.2
      Female311 (51.8%)151 (50.8%)160 (52.8%)3.9132 (52.2%)129 (51.0%)–2.4
      WHO performance status
       0443 (73.8%)224 (75.4%)219 (72.3%)–7.0188 (74.3%)189 (74.7%)0.9
       1145 (24.2%)69 (23.2%)76 (25.1%)4.361 (24.1%)61 (24.1%)0
       212 (2.0%)4 (1.3%)8 (2.6%)8.14 (1.6%)3 (1.2%)–2.5
      Histopathology
       Adenocarcinoma393 (65.5%)191 (64.3%)202 (66.7%)5.0177 (70.0%)189 (70.3%)1.7
       Squamous cell carcinoma132 (22.0%)71 (23.9%)61 (20.1%)–9.451 (20.2%)56 (20.8%)–2.0
       Large cell carcinoma15 (2.5%)10 (3.4%)5 (1.7%)–13.56 (2.4%)4 (1.5%)–3.1
       Small cell carcinoma6 (1.0%)5 (1.7%)1 (0.3%)–23.61 (0.4%)1 (0.4%)0
       Other or mixed54 (9.0%)20 (6.7%)34 (11.2%)14.218 (7.1%)19 (7.1%)1.3
      Type of surgery
       Lobectomy459 (76.5%)218 (73.4%)241 (79.5%)15.2197 (77.9%)206 (81.4%)8.8
       Sublobar resection95 (15.8%)59 (19.9%)36 (11.9%)–24.741 (16.2%)34 (13.4%)–8.6
       Bilobectomy16 (2.7%)8 (2.7%)8 (2.6%)–0.36 (2.4%)6 (2.4%)0
       Extended resection13 (2.2%)8 (2.7%)5 (1.7%)–8.15 (2.0%)5 (2.0%)0
       Pneumonectomy17 (2.8%)4 (1.3%)13 (4.3%)14.54 (1.6%)2 (0.8%)–3.9
      Surgical access
       VATS414 (69.0%)190 (64.0%)224 (73.9%)22.6170 (67.2%)197 (77.9%)24.1
       Open186 (31.0%)107 (36.0%)79 (26.1%)83 (32.8%)56 (22.1%)
      Cancer stage
      Cancer staging was based on the 8th Edition American Joint Commission on Cancer (AJCC) TNM system.11
       Tis11 (1.8%)6 (2.0%)5 (1.7%)–2.96 (2.4%)5 (2.0%)–3.1
       IA163 (10.5%)28 (9.4%)35 (11.6%)6.626 (10.3%)27 (10.7%)1.2
       IA2142 (23.7%)75 (25.3%)67 (22.1%)–7.666 (26.1%)60 (23.7%)–5.7
       IA3110 (18.3%)50 (16.8%)60 (19.8%)7.547 (18.6%)49 (19.4%)2.0
       IB63 (10.5%)29 (9.8%)34 (11.2%)4.626 (10.3%)29 (11.5%)3.8
       IIA29 (4.8%)13 (4.4%)16 (5.3%)4.012 (4.7%)13 (5.1%)1.8
       IIB95 (15.8%)53 (17.8%)42 (13.9%)–11.541 (16.2%)37 (14.6%)–4.6
       IIIA72 (12.0%)37 (12.5%)35 (11.6%)–2.825 (9.9%)26 (10.3%)1.2
       IIIB12 (2.0%)4 (1.3%)8 (2.6%)8.13 (1.2%)6 (2.4%)7.4
       IVA3 (0.5%)2 (0.7%)1 (0.3%)–6.01 (0.4%)1 (0.4%)0
      BMI, kg/m2, median ± IQR
      There was no BMI record in 45 patients. For the purpose of propensity score matching, median BMI value was imputed for these patients.
      24.8 ± 7.024.6 ± 8.024.8 ± 6.624.7 ± 8.124.2 ± 6.2
       BMI >30 kg/m29740 (13.5%)57 (18.8%)14.638 (15.0%)35 (13.8%)–3.0
      Comorbidities
       COPD149 (24.9%)80 (26.9%)69 (22.8%)9.662 (24.5%)62 (24.5%)0
       Inflammatory bowel disease3 (0.5%)2 (0.7%)1 (0.3%)4.91 (0.4%)1 (0.4%)0
       Previous VTE8 (1.3%)3 (1.0%)5 (1.7%)5.62 (0.8%)2 (0.8%)0
       Cardiovascular disease
      Cardiovascular diseases included hypertension, ischemic heart disease, and peripheral vascular disease.
      277 (46.2%)129 (43.4%)148 (48.8%)10.9113 (44.7%)124 (49.0%)8.7
       Previous/ongoing other malignancy136 (22.7%)65 (21.9%)71 (23.4%)3.751 (20.2%)61 (24.1%)9.5
       Estimated smoking pack y, median ± IQR
      There was no documented smoking data in 14 patients. In total, 28 patients were documented as current smokers and 92 as ex-smokers with no record of estimated pack years.
      30 ± 2930 ± 3725 ± 2515.930 ± 4130 ± 270
      Perioperative oncologic treatment10 (1.7%)3 (1.0%)7 (2.3%)10.23 (1.2%)3 (1.2%)0
      Postoperative complications
       LRTI111 (18.5%)43 (14.5%)68 (22.4%)20.641 (16.2%)45 (17.8%)3.8
       Stroke <1 mo onset5 (0.8%)4 (1.3%)1 (0.3%)11.22 (0.8%)1 (0.4%)–6.9
       Atrial fibrillation27 (4.5%)13 (4.4%)14 (4.6%)1.211 (4.3%)14 (5.5%)5.5
       Acute kidney injury13 (2.2%)3 (1.0%)10 (3.3%)15.82 (0.8%)6 (2.4%)12.7
      Postoperative LOS, d, median ± IQR5 ± 56 ± 45 ± 51.06 ± 54 ± 5–1.3
      Caprini RAM score, median ± IQR7 ± 27 ± 17 ± 107 ± 17 ± 20
       Low (≤4)2 (0.3%)2 (0.7%)02 (0.8%)0
       Medium (5-8)521 (86.8%)263 (88.6%)258 (85.1%)222 (87.7%)227 (89.7%)
       High (≥9)77 (12.8%)32 (10.8%)45 (14.9%)29 (11.5%)26 (10.3%)
      Time to CT, mo, median ± IQR5 ± 26 ± 25 ± 26 ± 26 ± 1
      Covariates used for matching included age, sex, BMI, WHO performance status, histopathology, type of surgery, cancer stage, perioperative oncological treatment, comorbidities (COPD, inflammatory bowel disease and history of previous VTE), postoperative complications (LRTI and stroke <1 month onset), Caprini RAM score, and postoperative length of stay. SMD, Standardized mean difference; SD, standard deviation; WHO, World Health Organization; VATS, video-assisted thoracoscopic surgery; BMI, body mass index; IQR, interquartile range; COPD, chronic obstructive pulmonary disease; VTE, venous thromboembolism; LRTI, lower respiratory tract infection; LOS, length of stay; RAM, risk assessment model; CT, computed tomography.
      Cancer staging was based on the 8th Edition American Joint Commission on Cancer (AJCC) TNM system.
      • Detterbeck F.C.
      • Boffa D.J.
      • Kim A.W.
      • Tanoue L.T.
      The eighth edition lung cancer stage classification.
      There was no BMI record in 45 patients. For the purpose of propensity score matching, median BMI value was imputed for these patients.
      Cardiovascular diseases included hypertension, ischemic heart disease, and peripheral vascular disease.
      § There was no documented smoking data in 14 patients. In total, 28 patients were documented as current smokers and 92 as ex-smokers with no record of estimated pack years.
      In the unmatched cohort, 15 (2.5%) VTE events were recorded, 11 (3.7%) in the control group and 4 (1.3%) in the treatment group. After matching, 1 VTE event was removed from each group, resulting in a total of 13 (2.6%) VTE events for analysis, 10 (4.0%) in the control group and 3 (1.2%) in the treatment group (Table 2). All 10 VTE events in the control group were PE, 6 within 28 days of the postoperative period, 1 at 5 months, and 3 at 6 months. Three VTE events recorded in the treatment group comprised 1 PE and 2 DVT. The recorded PE occurred within 28 days of the postoperative period. Both DVTs were incidental, one of which was an incidental central-line associated thrombus detected on CT chest to investigate chest sepsis at day 27 and the other, an incidental asymptomatic right femoral vein DVT detected during surveillance CT (chest, abdomen, and pelvis) at 6 months.
      Table 2Comparison of outcomes between control and treatment group
      VariablesUnmatchedP valueMatchedP value
      Control group (N = 297)Treatment group (N = 303)Control group (N = 253)Treatment group (N = 253)
      Pulmonary embolism11 (3.7%)2 (0.7%).0110 (4.0%)1 (0.4%).01
      Deep-vein thrombosis02 (0.7%).5002 (0.8%).50
      Death related to VTE4 (1.3%)0.063 (1.2%)0.25
      Postoperative mortality related to VTE2 (0.7%)0.242 (0.8%)0.50
      VTE within 28 d6 (2.0%)2 (0.7%).176 (2.4%)2 (0.8%).29
      PE within 28 d6 (2.0%)1 (0.3%).076 (2.4%)1 (0.4%).12
      Bleeding complications01 (0.3%)1.0001 (0.3%)1.00
      VTE events11 (3.7%)4 (1.3%).0710 (4.0%)3 (1.2%).09
       PE11 (100%)2 (50.0%).0610 (100%)1 (33.3%).04
       DVT02 (50.0%)02 (66.7%)
       VTE within 28 d6 (54.5%)2 (50.0%)1.006 (60.0%)2 (66.7%)1.00
       PE within 28 d6 (54.5%)1 (50.0%).576 (60.0%)1 (33.3%).56
       DVT within 28 d01 (50.0%).2701 (33.3%).23
       Time to VTE, d, median ± IQR24 ± 14745 ± 65.5622 ± 15227 ± 78.45
       Symptomatic VTE11 (100%)2 (50.0%).0610 (100%)1 (33.3%).04
       Death related to VTE4 (36.4%)0.273 (30.0%)0.53
      Cohorts before and after propensity score matching are included for comparison. VTE subgroups were analyzed. VTE, Venous thromboembolic; PE, pulmonary embolism; DVT, deep vein thrombosis; IQR, interquartile range.
      Following VTE diagnosis, patients were anticoagulated according to local guidelines with either direct oral anticoagulants, warfarin, or subcutaneous dalteparin at weight-adjusted therapeutic doses where oral alternatives were contraindicated. No VTE recurrence following treatment was identified. Patients were followed up by the thrombosis service to determine whether long-term anticoagulation was indicated.
      Extended chemoprophylaxis was associated with a significant reduction in the primary outcome of pulmonary embolic events compared with inpatient-only treatment (10 of 253 patients [4%] vs 1 of 253 patients [0.4%], P = .01), and a nonsignificant reduction in secondary outcome of overall VTE events (10 of 253 patients [4%] vs 3 of 253 patient [1.2%], P = .09). No VTE-associated mortality was observed in the treatment group, whereas 3 VTE-related deaths (1.2%) occurred in the control group (P = .25) (Table 2). There was no difference in patient characteristics between patients who developed fatal VTE and those who did not (Table E1). One patient (0.3%) in the treatment group developed upper gastrointestinal bleeding during extended chemoprophylaxis 10 days postoperatively. Endoscopic treatment was successfully instigated to a proximal duodenal (D1) ulcer with no further episodes of bleeding (Clavien–Dindo grade 3a complication).
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Dalteparin was restarted following cessation of bleeding and patient was discharged 4 days later. There were no further recorded bleeding complications in either group.
      Multivariable regression model demonstrated that extended thromboprophylaxis significantly reduced the incidence of postoperative PE (odds ratio [OR], 0.06; 95% confidence interval [CI], 0-0.44, P = .02) independent of age, sex, type of surgery, surgical access, histopathology, performance status, chronic obstructive pulmonary disease, postoperative length of stay, and postoperative LRTI. Other/mixed histopathology subtypes of lung cancer (OR, 10.3; 95% CI, 1.5-71.4, P = .01 compared with adenocarcinoma) and LRTI (OR, 7.0; 95% CI, 1.4-40.2, P = .02) were significant risk factors of postoperative PE (Figure 2).
      Figure thumbnail gr2
      Figure 2Odds ratio plot (and corresponding 95% confidence intervals) to evaluate the association of extended thromboprophylaxis with postoperative PE, adjusted for risk factors in the Caprini RAM. BMI, Body mass index; COPD, chronic obstructive pulmonary disease; VATS, video-assisted thoracoscopic surgery; PS, performance status; LOS, length of stay; LRTI, lower respiratory tract infection.
      Cumulative incidences of overall VTE and PE were plotted and demonstrated in Figure 3. Extended treatment was associated with a significant reduction in PE risk over time compared with the control group (log rank P < .01) and a nonsignificant reduction in VTE risk over time (log rank P = .055) (Figures 3 and 4). The majority of VTE events occurred within the first 28 days after surgery. Interestingly, an increased risk of VTE in both groups at approximately 6 months after the initial operation was also observed.
      Figure thumbnail gr3
      Figure 3Cumulative incidences of VTE (left) and PE (right) between control and treatment groups with corresponding 95% CIs. VTE, Venous thromboembolism; PE, pulmonary embolism; CI, confidence interval.
      Figure thumbnail gr4
      Figure 4Thromboembolic outcomes according to short duration or extended duration thromboprophylaxis in patients who underwent resection of primary lung cancer. PE, Pulmonary embolism; VTE, venous thromboembolism; OR, odds ratio; CI, confidence interval; CT, computed tomography.

      Discussion

      The known high incidence of VTE after major thoracic surgery prompted us to change our thromboprophylaxis protocols in our institution.
      • Raja S.
      • Idrees J.J.
      • Blackstone E.H.
      • He J.
      • Badjatiya A.
      • Mazzone P.
      • et al.
      Routine venous thromboembolism screening after pneumonectomy: the more you look, the more you see.
      ,
      • Agzarian 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.
      This retrospective, propensity-matched study has demonstrated that extended pharmacologic thromboprophylaxis for 28 days following resection of primary lung cancer is associated with a 10-fold reduction in incidence of PE, compared with the shorter postoperative inpatient regimen. The role for extended thromboprophylaxis in thoracic surgery is increasingly recognized and reinforced by the recent international Delphi consensus, but the ideal thromboprophylactic agent and its optimal duration remain uncertain.
      • Agzarian J.
      • Litle V.
      • Linkins L.A.
      • Brunelli A.
      • Schneider L.
      • Kestenholz P.
      • et al.
      International Delphi survey of the ESTS/AATS/ISTH task force on venous thromboembolism prophylaxis in thoracic surgery: the role of extended post-discharge prophylaxis.
      ,
      • Shargall Y.
      • Brunelli A.
      • Murthy S.
      • Schneider L.
      • Minervini F.
      • Bertolaccini L.
      • et al.
      Venous thromboembolism prophylaxis in thoracic surgery patients: an international survey.
      The majority of VTE events in our cohort occurred within 28 days of the postoperative period in both groups, consistent with findings in other studies.
      • Raja S.
      • Idrees J.J.
      • Blackstone E.H.
      • He J.
      • Badjatiya A.
      • Mazzone P.
      • et al.
      Routine venous thromboembolism screening after pneumonectomy: the more you look, the more you see.
      ,
      • Yang Y.
      • Zhou Z.
      • Niu X.M.
      • Li Z.M.
      • Chen Z.W.
      • Jian H.
      • et al.
      Clinical analysis of postoperative venous thromboembolism risk factors in lung cancer patients.
      This suggests there may be a critical role for extended thromboprophylaxis. By using rotational thromboelastometry, Mulder and colleagues
      • Mulder M.B.
      • Proctor K.G.
      • Valle E.J.
      • Livingstone A.S.
      • Nguyen D.M.
      • Van Haren R.M.
      Hypercoagulability after resection of thoracic malignancy: a prospective evaluation.
      studied hypercoagulability during the perioperative period in patients with resectable stages of lung cancer. They demonstrated hypercoagulability that persisted for at least 2 weeks following surgical resection. In advanced stages of lung cancer, the risk of VTE increases further.
      • Mulder M.B.
      • Proctor K.G.
      • Valle E.J.
      • Livingstone A.S.
      • Nguyen D.M.
      • Van Haren R.M.
      Hypercoagulability after resection of thoracic malignancy: a prospective evaluation.
      The ambiguity surrounding the optimal duration of extended thromboprophylaxis clearly warrants further research but extended thromboprophylaxis for at least 4 weeks after surgery appears justified.
      We observed a second peak in VTE incidence at approximately 6 months following surgery. This may be influenced by factors such as chronic obstructive pulmonary disease, smoking, and the intrinsic procoagulant effects of cancer in the case of patients who develop recurrence.
      • Dentali F.
      • Malato A.
      • Ageno W.
      • Imperatori A.
      • Cajozzo M.
      • Rotolo N.
      • et al.
      Incidence of venous thromboembolism in patients undergoing thoracotomy for lung cancer.
      VTE risk appears to be elevated for up to 12 months after surgery, and this is particularly true following cancer-related operations and in cases of incomplete resection.
      • Sweetland S.
      • Green J.
      • Liu B.
      • Berrington de Gonzalez A.
      • Canonico M.
      • Reeves G.
      • et al.
      Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study.
      The reasons for a reduced incidence of VTE events beyond 28 days for the duration of the study in the intervention group are not known and it is possible that despite propensity matching, unmeasured differences persist between the groups. A further possible reason is that postdischarge thromboprophylaxis administered either by patients or their relatives has caused an enhanced awareness in this group of patients to the risk of VTE, and there has been additional behavioral change in this group, resulting in a lower incidence of VTE.
      Bleeding is a recognized complication associated with anticoagulation and where extended thromboprophylaxis protocols are considered, this will be a concern. We recorded a single bleeding event within our cohort and following cessation of bleeding, LMWH was safely reinstated. While our study design did not screen for bleeding events, a similar safety profile has been demonstrated in other thoracic surgery cohorts and in guidelines involving major abdominal or pelvic surgery where prolonged thromboprophylaxis with LMWH is well-established and routinely used; the benefits of reduced VTE risk were not associated with increasing bleeding complications or mortality.
      • Felder S.
      • Rasmussen M.S.
      • King R.
      • Sklow B.
      • Kwaan M.
      • Madoff R.
      • et al.
      Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery.
      • Sterbling H.M.
      • Rosen A.K.
      • Hachey K.J.
      • Vellanki N.S.
      • Hewes P.D.
      • Rao S.R.
      • et al.
      Caprini Risk model decreases venous thromboembolism rates in thoracic surgery cancer patients.
      • Hachey K.J.
      • Sterbling H.
      • Choi D.S.
      • Pinjic E.
      • Hewes P.D.
      • Munoz J.
      • et al.
      Prevention of postoperative venous thromboembolism in thoracic surgical patients: implementation and evaluation of a Caprini risk assessment protocol.
      Bleeding assessment tools in surgical and oncological patients may be useful in clinical practice and this may be weighed against their postoperative VTE risk,
      • Kaatz S.
      • Ahmad D.
      • Spyropoulos A.C.
      • Schulman S.
      Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH.
      The role of the Caprini RAM in lung cancer resection surgery may be limited since most patients (up to 99%) have moderate (5-8) to high (≥9) Caprini scores. While a tailored approach of VTE chemoprophylaxis based on the patient's Caprini score has been shown to be effective, there are risk factors specific to lung cancer patients that are not accounted for within the Caprini model.
      • Sterbling H.M.
      • Rosen A.K.
      • Hachey K.J.
      • Vellanki N.S.
      • Hewes P.D.
      • Rao S.R.
      • et al.
      Caprini Risk model decreases venous thromboembolism rates in thoracic surgery cancer patients.
      ,
      • Hachey K.J.
      • Sterbling H.
      • Choi D.S.
      • Pinjic E.
      • Hewes P.D.
      • Munoz J.
      • et al.
      Prevention of postoperative venous thromboembolism in thoracic surgical patients: implementation and evaluation of a Caprini risk assessment protocol.
      ,
      • Pannucci C.J.
      • Swistun L.
      • MacDonald J.K.
      • Henke P.K.
      • Brooke B.S.
      Individualized venous thromboembolism risk stratification using the 2005 caprini score to identify the benefits and harms of chemoprophylaxis in surgical patients: a meta-analysis.
      We identified other/mixed histopathology subtypes as an independent risk factor for postoperative VTE, whereas in other studies, hematologic parameters such as platelet count and operative factors such as pneumonectomy and open approach may also serve predictive roles.
      • Thomas 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.
      ,
      • Tesselaar M.E.T.
      • Osanto S.
      Risk of venous thromboembolism in lung cancer.
      ,
      • Vitale C.
      • D'Amato M.
      • Calabrò P.
      • Stanziola A.A.
      • Mormile M.
      • Molino A.
      Venous thromboembolism and lung cancer: a review.
      Further research into a specific risk stratification model tailored to thoracic surgery patients may, therefore, be of use to identify patients at greatest risk of VTE and at most benefit from extended thromboprophylaxis.
      Our study is subject to the attendant biases of retrospective design. While the postoperative VTE event rate in the study is low, the association of these events with postoperative morbidity and mortality is clinically important. No data are available regarding patient compliance with extended thromboprophylaxis however, lack of compliance would serve to underestimate benefit in the extended group. Furthermore, compliance with extended pharmacologic thromboprophylaxis has been shown to be high in other studies.
      • Sterbling H.M.
      • Rosen A.K.
      • Hachey K.J.
      • Vellanki N.S.
      • Hewes P.D.
      • Rao S.R.
      • et al.
      Caprini Risk model decreases venous thromboembolism rates in thoracic surgery cancer patients.
      It is possible that subclinical VTE events were not identified but arguably, symptomatic VTEs are of most concern. If this intervention were to be implemented on a larger scale, cost-effectiveness should be considered. Whilst the Caprini RAM and propensity matching process aimed to account for differences between the 2 groups, it remains possible that unaccounted for differences between the groups are an explanation for the greater rate of thromboembolic events beyond the 28 days of extended prophylaxis, in particular SMD of surgical access (video-assisted thoracoscopic surgery vs open) was 24.1%. However, sensitivity analysis for unmeasured confounding with E-value found that moderate confounding would be needed to change our primary outcome result (E-value 19.5, upper confidence limit 1.9).
      • VanderWeele T.J.
      • Ding P.
      Sensitivity analysis in observational research: introducing the E-value.
      Although variation in ethnicity may account for differences in VTE between groups, ethnicity was White in 97% in a similar institutional surgical cohort.
      • Belcher E.
      • Mitchell J.
      • Stavroulias D.
      • Di Chiara F.
      • Rahman N.
      Optimal resection rate for lung cancer in the UK: how high should we go?.
      Finally, cancer recurrence rates were not analyzed in our cohort, which may be a contributing factor to VTE events observed several months following resection.

      Conclusions

      Patients undergoing lung cancer resection are at moderate-to-high risk of postoperative VTE, with the greatest risk period within the first 28 days following operation. We have demonstrated that extended dalteparin for 28 days is safe and is associated with a significant 10-fold reduction in incidence of PE in patients undergoing resection of early-stage primary lung cancer. We recommend consideration of extended VTE thromboprophylaxis in patients undergoing resection of early-stage lung cancer to reduce important thromboembolic events.

      Conflict of Interest Statement

      The authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

      Appendix E1

      Table E1Fatal VTE versus nonfatal VTE in the matched cohort
      VariablesNonfatal VTE (%)Fatal VTE (%)
      N103
      Age, y, median ± IQR70 ± 1371 ± 8
      Female5 (50.0)1 (33.3)
      Male5 (50.0)2 (66.7)
      WHO performance status
       05 (50.0)1 (33.3)
       15 (50.0)1 (33.3)
       201 (33.3)
      Histopathology
       Adenocarcinoma3 (30.0)1 (33.3)
       Squamous cell carcinoma4 (40.0)1 (33.3)
       Small cell carcinoma1 (10.0)0
       Other or mixed2 (20.0)1 (33.3)
      Type of surgery
       Lobectomy5 (50.0)3 (100)
       Sublobar resection3 (30.0)0
       Others2 (20.0)0
      Surgical access
       VATS3 (30.0)2 (66.7)
       Open7 (70.0)1 (33.3)
      Cancer stage
       Tis-IIA6 (60.0)2 (66.7)
       IIB-IVA4 (40.0)1 (33.3)
      Postoperative LOS, median ± IQR12 ± 1611 ± 18
      BMI > 30 kg/m23 (30.0)1 (33.3)
      COPD3 (30.0)1 (33.3)
      Previous VTE1 (10.0)0
      LRTI7 (70.0)1 (33.3)
      VTE, Venous thromboembolism; IQR, interquartile range; WHO, World Health Organization; VATS, video-assisted thoracoscopic surgery; LOS, length of stay; BMI, body mass index; COPD, chronic obstructive pulmonary disease; LRTI, lower respiratory tract infection.

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      Linked Article

      • Commentary: Extended thromboembolism chemoprophylaxis for thoracic oncologic surgery: To discharge and beyond!
        The Journal of Thoracic and Cardiovascular SurgeryVol. 164Issue 6
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          Venous thromboembolic (VTE) events are a major complication following thoracic oncologic surgery and are associated with significant morbidity and mortality.1 Despite current guidelines recommending the use of inpatient pharmacologic thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparin,2 studies have estimated that up to 15% of patients seeking surgical thoracic oncology care will develop a VTE complication postoperatively and nearly a quarter of these events are anticipated to occur after discharge.
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