How to Mitigate the Risk of Postoperative Thromboembolism in Thoracic Cancer Surgery: Comments on the Joint 2022 European Society of Thoracic Surgery and American Association of Thoracic Surgery Guidelines for the Prevention of Cancer-Associated Venous Thromboembolism in Thoracic Surgery

Abstract

Venous thromboembolic events (VTE) manifesting as deep venous thrombosis (DVT) and pulmonary embolism (PE) are important complications in patients after major surgery, which are potentially devastating.1-3 The importance of preventive measures has been recognized for decades, and thromboprophylaxis in the early postoperative period can reduce the risk of VTE by up to 70%.1,4,5 However, even with prophylactic administration of anticoagulants, VTE after major surgery remains common and might account for up to 25% of all VTEs observed in the general population.6 In addition, the advantage of pharmacological thromboprophylaxis must be balanced against the increased risk of postoperative bleeding.1 Patients undergoing thoracic surgery represent a subset of patients with high risk of postoperative thromboembolic complications.7,8 A large percentage of these patients has advanced malignancies, accompanying comorbidities like chronic obstructive pulmonary disease and pulmonary hypertension, extensive surgical resection, prolonged immobilization, and requirement for longer hospitalization.7 These risk factors together with tumor-associated hypercoagulability, endothelial injury, and venous stasis, summarized as the “Virchow's triad”, increase the risk of fatal VTE. Timely and adequate preventive measures are advised,8,9 but the evidence for optimal VTE prophylaxis in thoracic surgery patients is limited and primarily based on clinical consensus.1,9 Accordingly, institutional practices of VTE prophylaxis vary widely.7,8 The recently published guidelines by a Joint Committee of the European Society of Thoracic Surgery (ESTS) and the American Association of Thoracic Surgery (AATS)10 highlight some of the ambiguity of this clinically relevant problem. In these guidelines, three clinical settings in patients with cancer-associated thoracic surgery (lobectomy/segmentectomy, pneumonectomy/extended lung resections, and esophagectomy) were evaluated for the following five interventions: I) pharmacological prophylaxis, II) mechanical prophylaxis, III) duration of prophylaxis, IV) pre- vs post-operative administration of prophylaxis, and V) routine post-operative screening for VTE. An abbreviated summary of the most important recommendations is given in Table 1. Notably, the recommendations given in these guidelines are mostly conditional rather than strong and are based on low to very low certainty of evidence.Table 1Short Summary of Suggestions from the Joint 2022 ESTS/AATS GuidelinesLobectomy/segmentectomyPneumonectomy/EsophagectomyPharmacological prophylaxisUse LMWH (or UFH sc)Conditional recommendation, low certaintyUse LMWH (or UFH sc)Conditional recommendation, low certaintyUse LMWH (or UFH sc)Conditional recommendation, low certaintyMechanical prophylaxisUse combined mechanical and pharmacological prophylaxisConditional recommendation, very low certaintyUse combined mechanical and pharmacological prophylaxisConditional recommendation, very low certaintyUse combined mechanical and pharmacological prophylaxisConditional recommendation, very low certaintyDurationExtended prophylaxis (28-35 days) in patients with moderate to high thromboembolic riskConditional recommendation, low certaintyExtended prophylaxis (28-35 days)Conditional recommendation, low certaintyExtended prophylaxis (28-35 days)Conditional recommendation, low certaintyPre- v postoperative pharmacological prophylaxisNo recommendationNo recommendationNo recommendationRoutine postoperative screening for VTENo routine screeningConditional recommendation, very low certaintyRoutine screening suggestedConditional recommendation, very low certaintyRoutine screening suggestedConditional recommendation, very low certaintyAbbreviations: LMWH, low molecular weight heparin; sc, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolic events Open table in a new tab Abbreviations: LMWH, low molecular weight heparin; sc, subcutaneous; UFH, unfractionated heparin; VTE, venous thromboembolic events The reported incidence of VTEs following thoracic surgery including lung resection relevantly varies with reported incidences of 0.2% to 27% with a mean risk of 2 to 4%.7,9,11,12 The performed surgery (cancer vs non-cancer, open vs minimally invasive), implementation of early recovery after surgery (ERAS) programs, and cancer characteristics might relevantly influence postoperative VTE risk.13,14 For example, pneumonectomy was associated with a 3-times increased VTE risk compared to lobectomy in a large retrospective database analysis, and open resection had higher risk than minimally invasive resections.15 For minimally invasive thoracic surgery, perioperative coagulation activation might be lowest.13 Further, the different methods of detecting venous thromboembolism (routine screening vs symptomatic patients only), type of post-operative prophylaxis (pharmacological and/or mechanical), and timing of thromboprophylaxis might explain the highly variable VTE incidences. As VTE is a major complication after cancer surgery, perioperative VTE prophylaxis is considered a standard of care in most guidelines.4,16-18 Accordingly, more than 85% of European and US centers performing thoracic cancer surgery had formal institutional VTE prophylaxis protocols based on the presumably best evidence.8 However, there is a lack of consensus with respect to timing and dosing of perioperative prophylaxis and, more importantly, to extended VTE prophylaxis after hospital discharge.7-9,15,19 Patients undergoing thoracic surgery for cancer deserve special consideration as hemostatic abnormalities manifesting with hypercoagulability and/or bleeding disorders occur in most cancer patients.1,20 The pathogenesis of blood coagulation activation in cancer is complex, multifactorial, and still not fully understood.20 It might also vary with cancer type and stage. However, recently published guidelines from the European Association of Anaesthesiology and Intensive Care (EACTAIC), the American College of Chest Physicians (ACCP), the American Society of Hematology (ASH), and the American Society of Clinical Oncology (ASCO) did not specifically consider such factors.16,18,21,22 The Joint 2022 ESTS/AATS guidelines focused for the first time specifically on patients undergoing different clinical situations of cancer-associated thoracic surgery and provided evidence for specific conditions regarding perioperative thromboprophylaxis.10 In the Joint 2022 ESTS/AATS guidelines, the use of low molecular weight heparin (LWMH) is suggested.10 Subcutaneously administered unfractionated heparin (UFH) could be considered as an alternative but with lower evidence for efficacy.10 The preference for LMWH might be based on data derived from general surgery patients that were included in randomized trials and meta-analyses.23 Most of them showed a similar or superior efficacy of LMWH compared to UFH. However, direct evidence for using LMWH preferably to UFH in thoracic surgery patients is limited. A survey among Canadian specialists in perioperative care of thoracic cancer surgery showed that only 44% of practitioners used LWMH once daily, whereas about 53% of physicians preferred the subcutaneous administration of UFH 2 to 3 times daily.7 Further, optimal dosing and perioperative timing of pharmacological VTE prophylaxis are unclear.24 A preoperative administration of LMWH for VTE prophylaxis seems common in clinical practice,7,8 but evidence for its beneficial effects is scarce. Similarly, the optimal dosing remains unclear. A recent study in thoracic surgery patients concluded that commonly applied LWMH dose (40 mg of enoxaparin) might be insufficient to protect most patients adequately from VTE.25 This conclusion was based on testing of anti-Xa activity only.25 In some agreement, a small randomized controlled trial (RCT) investigating prophylaxis with LWMH (dalteparin 5000 U once daily) vs no prophylaxis found no differences in coagulation profile between the two groups.26 Evaluation of thromboembolic events rather than changes in coagulation tests might be of more clinical relevance. Unfortunately, the number of included patients was too low for meaningful clinical conclusions.26 Another RCT in 111 patients undergoing esophagectomy compared LMWH (nadroparin) twice a day (intensified prophylaxis) with once a day only (standard of care) starting 6 hours after surgery. VTE prophylaxis was continued until day 7 after surgery. The authors found significantly less VTE with intensified prophylaxis as compared to standard care (0% vs 9%, p = 0.03).27 The Joint 2022 ESTS/AATS did not make specific recommendations on dosage or targets of anticoagulation.10 Potentially, the individualized VTE prophylaxis based on factors such as the timing (elective or emergency), type and duration of surgery, the estimated risk of bleeding, and especially the patient's baseline risk of VTE (eg, Caprini score28,29) seems more recommendable.10,11,26,28 Recently, the extended VTE prophylaxis has gained specific attention. In a large retrospective database analysis including more than 14,000 patients undergoing lung cancer surgery, 44% of identified VTE occurred after hospital discharge.15,30 The use of extended out-of-hospital prophylaxis for 4 to 6 weeks after surgery is an established and recommended practice in other surgical specialties such as high-risk orthopedic and major oncologic abdominal surgery.22 In thoracic surgery, surveys reported no agreement among perioperative chest physicians regarding recommended agents or factors mandating usage of extended VTE prophylaxis.7,8 A recent study in patients undergoing lung cancer surgery showed that extended VTE prophylaxis with LMWH (dalteparin) for 28 days was safe and might have reduced the incidence of pulmonary embolism.19 Alternatively, the use of fondaparinux is recommended by the British National Institute for Health and Clinical Excellence (NICE) for extended VTE prophylaxis in thoracic cancer surgery.31 The optimal length of prophylaxis, however, remains unclear. The Joint 2022 ESTS/AATS guidelines suggested an extended prophylaxis for 28 to 35 days in patients undergoing lobectomy/segmentectomy and moderate to high thromboembolic risk as well as all patients undergoing pneumonectomy, extended lung surgery, and esophagectomy. At the authors’ institution, VTE prophylaxis up to 6 months is sometimes used in patients after pneumonectomy who are at high risk for thromboembolism or pulmonary hypertension. The long-term use of LMWH or fondaparinux might be acceptable for most patients. However, oral anticoagulants might be preferred for extended VTE prophylaxis. Notably, the optimal range of anticoagulation level (international normalized ratio, INR) during prophylactic therapy with vitamin K antagonists is not known, and experience with the use of direct oral anticoagulants (DOAC) is limited. Clinical data and studies with DOACs are limited to non-thoracic surgery32,33 and are urgently warranted in thoracic cancer surgery before further recommendations can be made.10 Finally, the clinical burden of postoperative VTE in thoracic surgery is most probably underestimated.15 Perioperative and postoperative VTE can be asymptomatic, which may be the reason for the low incidence of postoperative VTE reported in some studies. It is unclear whether asymptomatic VTE have the same clinical impact as symptomatic VTE. However, evidence suggesting a systematic screening in all thoracic surgery patients does not (yet) exist. The Joint 2022 ESTS/AATS guidelines specifically suggest a VTE screening in patients after in pneumonectomy, extended lung surgery, and esophagectocy.10 The optimal diagnostic test (eg, computed tomography with pulmonary angiogram and/or ultrasound) remains to be defined. Of note, the sensitivity of modern computed tomography devices bears the risk of overtreatment with anticoagulants in patients with clinically irrelevant emboli. It remains unclear whether the increased bleeding risk outweighs the beneficial effect of antithrombotic therapy. Recently, guidelines regarding postoperative thromboembolism prophylaxis from four important societies were published. The ACCP guidelines recommend the use of in-hospital routine VTE prophylaxis with either low-dose UFH or LMWH for the post-operative thoracic surgery population (grade 1B evidence).17 In the updated ACCP guidelines, no further specific recommendation in respect to thromboembolic prophylaxis in thoracic surgery were given.4 The ESAIC guidelines from 2019 suggested the use of a combined pharmacological and mechanical VTE prophylaxis (grade 2B recommendation) given that most patients undergoing thoracic surgery should be considered belonging to the high-risk population for VTE.16 In agreement with the Joint 2022 ESTS/AATS guidelines, mechanical prophylaxis without pharmacological prophylaxis should only be used in patients with contraindications for pharmacological VTE prophylaxis (recommendation 1B).16 Of note, the ESAIC guidelines suggested not differentiating between patients undergoing open or thoracoscopic cancer-associated thoracic surgery with respect to risk stratification.16 Finally, the ESAIC guidelines support early ambulation as part of an ERAS program to potentially reduce the VTE risk in thoracic surgery.14 The 2019 ASH guidelines for the management of VTE did not specifically comment on the perioperative VTE prevention in thoracic surgery. In partial agreement with the ESTS/AATS and the ESAIC guidelines, the ASH guidelines suggested a combined pharmacological and mechanical prophylaxis over pharmacological alone, and an extended (considered as >3 weeks) prophylaxis in major surgery. However, both recommendations were conditional with low certainty.18 Finally, ASCO recommended in their 2019 guidelines that all patients with malignant diseases undergoing major surgery (including thoracic) should receive pharmacological thromboprophylaxis with LMWH or UFH unless contraindicated by active bleeding or high bleeding risk (strong recommendation). Again, these guidelines recommended the combined pharmacological and mechanical approach to potentially improve efficacy, especially in the highest-risk population (strong recommendation). An extended prophylaxis for up to 4 weeks has specifically been recommended for abdominal and pelvic cancer surgery but not for thoracic cancer surgery.22 The Joint 2022 ESTS/AATS guidelines provide valuable evidence-based recommendations in patients undergoing thoracic surgery for lung and esophageal cancer. This population at high risk for VTE has not been adequately considered in most former guidelines that issued recommendations on the VTE prevention in major surgery and in cancer patients undergoing surgery. However, their evidence is limited, partially controversial, and based on experts’ opinions. An individual and adapted VTE prophylaxis might be considered in many patients undergoing lung cancer surgery based on hemostatic history, lung and pulmonary vascular morbidity, resection type, and general physical condition. Potentially, application risk scores such as the Caprini score could help to select patients who might qualify for postoperative VTE screening and for intensified and/or extended prophylaxis.28,29 Further clinical trials are vital to further support the evidence behind our medical decisions.