Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline

Abstract

•Cancer-associated thrombosis is a major health problem that affects morbidity and mortality of people with cancer.•Surgical and systemic pharmacological anticancer treatments have a significant impact on the thrombotic risk of patients.•Primary thromboprophylaxis may be considered in high-risk ambulatory cancer patients using validated risk models.•Anticoagulant treatment of venous thromboembolism in cancer patients is effective but may be associated with increased bleeding.•LMWH or DOACs are effective treatments and generally safe options for cancer-associated thrombosis. Thromboembolism in people with cancer still remains a major health problem and figures as a leading cause of mortality after cancer itself, despite being a largely preventable disease.1Khorana A.A. Francis C.W. Culakova E. et al.Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy.Journal of thrombosis and haemostasis : JTH. 2007; 5: 632-634Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar A hypercoagulable state is the hallmark of cancer. It is induced by specific prothrombotic properties of cancer cells that activate blood clotting, as schematically depicted in Figure 1. These properties include the expression and release of procoagulant molecules, the activation of host blood and vascular cells (i.e. platelets, leukocytes and endothelial cells), which enhances their procoagulant potential, and the activation of the endothelium by anti-cancer drugs.2Falanga A. Schieppati F. Russo L. Pathophysiology 1. Mechanisms of Thrombosis in Cancer Patients.Cancer Treat Res. 2019; 179: 11-36Crossref PubMed Scopus (34) Google Scholar The risk of venous thromboembolism (VTE) is higher in individuals with cancer than in those without cancer across all age categories. Over the last two decades, the risk of VTE in people with cancer has increased 3-fold and is 9-fold higher than in the general population.3Mulder F.I. Horváth-Puhó E. van Es N. et al.Venous thromboembolism in cancer patients: a population-based cohort study.Blood. 2021; 137: 1959-1969Crossref PubMed Scopus (113) Google Scholar The mortality rate of people with cancer with VTE is 2- to 3-fold higher compared with those without VTE.3Mulder F.I. Horváth-Puhó E. van Es N. et al.Venous thromboembolism in cancer patients: a population-based cohort study.Blood. 2021; 137: 1959-1969Crossref PubMed Scopus (113) Google Scholar In addition, anticoagulant treatment for a VTE event in patients with solid tumours is complicated because these patients have both an increased risk of thrombotic recurrences and bleeding during therapeutic anticoagulation.4Ay C. Beyer-Westendorf J. Pabinger I. Treatment of cancer-associated venous thromboembolism in the age of direct oral anticoagulants.Ann Oncol. 2019; 30: 897-907Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar The thrombotic risk varies according to the cancer type (patients with pancreatic, gastric or lung cancer or primary brain tumours are among those with the highest risk); the actual burden of cancer-associated thrombosis (CAT) in the community is driven, however, by the common malignancies such as breast, prostate, colorectal and lung cancers, which largely contribute to the overall prevalence of CAT.5Cohen A.T. Katholing A. Rietbrock S. et al.Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study.Thrombosis and haemostasis. 2017; 117: 57-65Crossref PubMed Scopus (0) Google Scholar People with cancer who undergo surgical resection are at significantly higher risk of peri- and post-operative VTE than patients who undergo surgery for non-malignant diseases.6Kakkar A.K. Haas S. Wolf H. et al.Evaluation of perioperative fatal pulmonary embolism and death in cancer surgical patients.Thrombosis and haemostasis. 2005; 94: 867-871PubMed Google Scholar,7Merkow R.P. Bilimoria K.Y. McCarter M.D. et al.Post-discharge venous thromboembolism after cancer surgery: extending the case for extended prophylaxis.Ann Surg. 2011; 254: 131-137Crossref PubMed Scopus (160) Google Scholar Patient-related risk factors including comorbidities—such as presence of cardiovascular disease or cardiovascular risk factors (i.e. diabetes, hypertension, obesity, dyslipidaemia)—contribute to the risk of CAT. More recently, certain single nucleotide polymorphisms in coagulation-related genes have been associated with the risk of CAT (Supplementary Table S1). Oncogenic mutations and rearrangements are also associated with a substantial increase of risk for CAT (Supplementary Table S1). CAT complicates the management of anticancer therapies and is associated with substantial increase of expenditure for the healthcare systems.8Lyman G.H. Culakova E. Poniewierski M.S. et al.Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer.Thrombosis research. 2018; 164: S112-S118Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Preventing VTE in people with cancer by pharmacological and non-pharmacological measures is a challenging and crucial issue. It is important to identify patients in the highest risk categories, who can most benefit from primary thromboprophylaxis. The efficacy and safety of direct oral anticoagulants (DOACs) inhibiting Xa have been recently tested for the treatment of CAT and offer an alternative to low molecular weight heparin (LMWH).9Becattini C. Di Nisio M. Franco L. et al.Treatment of venous thromboembolism in cancer patients: The dark side of the moon.Cancer treatment reviews. 2021; 96102190Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,10Verso M. Munoz A. Bauersachs R. et al.Effects of concomitant administration of anticancer agents and apixaban or dalteparin on recurrence and bleeding in patients with cancer-associated venous thromboembolism.Eur J Cancer. 2021; 148: 371-381Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The approval status of the agents discussed in this guideline might differ from country to country. With a focus on ease of implementation, this updated ESMO Clinical Practice Guideline (CPG) summarises recommendations for prevention and treatment of VTE in patients with cancer. VTE includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Clinical manifestations of DVT of the legs include redness, tenderness, swelling, pitting oedema and appearance of collateral superficial veins; while manifestations of PE are dyspnoea, chest pain, cough, tachycardia, cyanosis, dizziness, fainting and excessive sweating. The diagnosis of VTE, however, cannot rely on the clinical manifestations alone as the signs and symptoms are not specific. Imaging is necessary to confirm the diagnosis. In the general population, diagnostic algorithms consisting of clinical probability assessment and D-dimer testing have been established to guide decisions about who should be referred for compression ultrasonography (CUS) in case of suspected DVT and computed tomography (CT) pulmonary angiography (CTPA) in case of suspected PE.11Di Nisio M. van Es N. Büller H.R. Deep vein thrombosis and pulmonary embolism.Lancet. 2016; 388: 3060-3073Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar For comparison, the diagnostic algorithm for non-cancer patients is reported in Supplementary Figure S1. Unfortunately, in cancer patients the performance of clinical decision rules and D-dimer testing is poor.12Geersing G.J. Zuithoff N.P. Kearon C. et al.Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.BMJ. 2014; 348: g1340Crossref PubMed Scopus (135) Google Scholar As a consequence, in these patients, physicians should consider proceeding to CUS and CTPA directly (Figure 2). •In cancer patients, diagnosis by CUS in case of suspected DVT and diagnosis by CTPA in case of suspected PE, without using clinical prediction rules and D-dimer level, are recommended [I, A]. Table 1 shows available pharmacological and mechanical VTE prophylaxis options.Table 1VTE prophylaxis options in cancer patientsOptionsHospitalised patientsSurgical patientsAmbulatory patientsHeparinsaUFH5000 IU every 8 hours5000 IU 2-4 hours preoperatively and every 8 hours thereafter-Bemiparin3500 anti-Xa IU od3500 anti-Xa IU starting 2 hours preoperatively or 6 hours post-operatively and 3500 anti-Xa IU od thereafter3500 anti-Xa IU odbDalteparin5000 anti-Xa IU od5000 anti-Xa IU 12 hours preoperatively and 5000 anti-Xa IU od thereafter5000 anti-Xa IU odb,cEnoxaparin4000 anti-Xa IU od4000 anti-Xa IU 12 hours preoperatively and 4000 anti-Xa IU od thereafter4000 anti-Xa IU odbNadroparin3800 anti-Xa IU od (if weight >70 kg 5700 anti-Xa IU/kg od)2850 anti-Xa IU 2-4 hours preoperatively and 2850 anti-Xa IU od thereafter3800 anti-Xa IU od (if weight >70 kg 5700 anti-Xa IU od)bTinzaparin4500 anti-Xa IU od4500 anti-Xa IU od, beginning 12 hours post-operatively4500 anti-Xa IU odbSelective parenteral indirect factor Xa inhibitorFondaparinux2.5 mg od2.5 mg od beginning6-8 hours post-operativelyNot studied in the outpatient prophylaxis settingDOACsApixabanNot recommendedNot recommended2.5 mg orally bdbRivaroxabanNot recommendedNot recommended10 mg orally odbMechanical prophylaxisIPCIf pharmacological VTE prophylaxis is contraindicateddIf pharmacological VTE prophylaxis is contraindicateddNot recommendedVenous foot pumpIf pharmacological VTE prophylaxis is contraindicateddIf pharmacological VTE prophylaxis is contraindicateddNot recommendedGCSsIf pharmacological VTE prophylaxis is contraindicateddIf pharmacological VTE prophylaxis is contraindicateddNot recommendedbd, twice daily; DOAC, direct oral anticoagulant; GCS, graduated compression stocking; IPC, intermittent pneumatic compression; od, once daily; UFH, unfractionated heparin; VTE, venous thromboembolisma Approved indications and dosages of anticoagulants may vary across different countries.b Lack of a specific indication for cancer outpatients in the package inserts.c In pancreatic cancer, higher doses have been used in clinical trials in this setting.d Some patients may also have a contraindication for mechanical prophylaxis (e.g. patients with peripheral limb ischaemia). Open table in a new tab bd, twice daily; DOAC, direct oral anticoagulant; GCS, graduated compression stocking; IPC, intermittent pneumatic compression; od, once daily; UFH, unfractionated heparin; VTE, venous thromboembolism a Approved indications and dosages of anticoagulants may vary across different countries. b Lack of a specific indication for cancer outpatients in the package inserts. c In pancreatic cancer, higher doses have been used in clinical trials in this setting. d Some patients may also have a contraindication for mechanical prophylaxis (e.g. patients with peripheral limb ischaemia). General considerations. Assessment of the risk of thrombosis and bleeding should be carried out before any surgical procedure, including cancer surgery. The following factors are to be considered:•Patient risk factors [i.e. by risk assessment models (RAMs)], e.g. the Caprini score13Sterbling H.M. Rosen A.K. Hachey K.J. et al.Caprini Risk Model Decreases Venous Thromboembolism Rates in Thoracic Surgery Cancer Patients.The Annals of Thoracic Surgery. 2018; 105: 879-885Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar; see also Supplementary Material, Supplementary Tables S2 and S3 and Supplementary Figure S2)•Type of intervention (minor surgery = open or laparoscopic of <45 minutes duration; or major surgery = open or laparoscopic of >45 minutes duration)•Contraindications to pharmacological thromboprophylaxis (e.g. active bleeding, acute hepatitis or acquired haemophilic states, uncontrolled hypertension, acute stroke, platelet count <25,000 μl, lumbar puncture or spinal/epidural anaesthesia in the next 12 hours or in the previous 4 hours, ongoing anticoagulant treatment for other indications) Pharmacological thromboprophylaxis with LMWH or unfractionated heparin (UFH) is standard of care in surgical patients with a high risk of VTE and a low risk of bleeding. Malignancy is associated with an increased risk for both thromboembolic and haemorrhagic complications. Thus, particular caution is warranted in patients undergoing major cancer surgery, since the overall risk–benefit ratio of pharmacological thromboprophylaxis may be less clear in cancer versus non-cancer surgical patients. A recent systematic review and meta-analysis of randomised controlled trials (RCTs) specifically conducted in surgical cancer patients concluded that LMWH, in comparison with no prophylaxis or mechanical prophylaxis, decreased the rates of DVT [relative risk (RR) 0.20, 95% confidence interval (CI) 0.07-0.61] and PE (RR 0.13, 95% CI 0.01-2.25), but potentially increased the risk of major bleeding (RR 2.47, 95% CI 0.08-74.18).14Guo Q. Huang B. Zhao J. et al.Perioperative Pharmacological Thromboprophylaxis in Patients With Cancer: A Systematic Review and Meta-analysis.Annals of Surgery. 2017; 265: 1087-1093Crossref PubMed Scopus (0) Google Scholar No data support the superiority of any LMWH over the other. Similarly, subcutaneous LMWH once daily (od) and subcutaneous UFH three times daily (tds) have comparable efficacy when used perioperatively in cancer patients.15Akl E.A. Kahale L.A. Sperati F. et al.Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer.Cochrane Database of Systematic Reviews. 2014; Google Scholar Two meta-analyses have shown no difference between LMWH and UFH regarding mortality, PE and bleeding, but found a lower incidence of wound haematoma with LMWH prophylaxis (RR 0.70, 95% CI 0.54-0.92).14Guo Q. Huang B. Zhao J. et al.Perioperative Pharmacological Thromboprophylaxis in Patients With Cancer: A Systematic Review and Meta-analysis.Annals of Surgery. 2017; 265: 1087-1093Crossref PubMed Scopus (0) Google Scholar,16Matar C.F. Kahale L.A. Hakoum M.B. et al.Anticoagulation for perioperative thromboprophylaxis in people with cancer.Cochrane Database Syst Rev. 2018; 7: CD009447PubMed Google Scholar LMWHs have a lower risk of heparin-induced thrombocytopaenia and a more convenient administration schedule, which makes them an attractive first-choice agent. There are limited data supporting the efficacy of fondaparinux for VTE prophylaxis in cancer patients undergoing surgery. In a meta-analysis of three RCTs of fondaparinux versus LMWH for perioperative thromboprophylaxis, no statistically significant difference was found, but the certainty of evidence was low.16Matar C.F. Kahale L.A. Hakoum M.B. et al.Anticoagulation for perioperative thromboprophylaxis in people with cancer.Cochrane Database Syst Rev. 2018; 7: CD009447PubMed Google Scholar There are no data so far on the efficacy and safety of DOACs in cancer surgery. Mechanical methods such as intermittent pneumatic compression (IPC) or graduated compression stockings (GCSs) may represent an appealing option for VTE prophylaxis due to their minimal risk of haemorrhage. There is insufficient evidence, however, to support the use of mechanical methods as monotherapy in place of pharmacological VTE prophylaxis in major cancer surgery, unless there are contraindications to anticoagulation. Small RCTs in cancer surgical patients have shown the superiority of LMWH over IPC alone in reducing the occurrence of VTE complications.17Nagata C. Tanabe H. Takakura S. et al.Randomized controlled trial of enoxaparin versus intermittent pneumatic compression for venous thromboembolism prevention in Japanese surgical patients with gynecologic malignancy.J Obstet Gynaecol Res. 2015; 41: 1440-1448Crossref PubMed Scopus (28) Google Scholar,18Sakon M. Kobayashi T. Shimazui T. Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study.Thrombosis research. 2010; 125: e65-e70Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In patients at high risk of VTE (e.g. following surgery, trauma or intensive care unit admission), adding IPC to pharmacological prophylaxis, as compared with pharmacological prophylaxis alone, decreases the incidence of PE [odds ratio (OR) = 0.39, 95% CI 0.23-0.64) and DVT (OR = 0.42, 95% CI 0.18-1.03), without increasing the incidence of major bleeding (OR = 1.21, 95% CI 0.35-4.18).19Kakkos S.K. Caprini J.A. Geroulakos G. et al.Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism.Cochrane Database Syst Rev. 2016; 9Cd005258PubMed Google Scholar Combined prophylaxis, however, is rarely used in daily clinical practice in oncology patients. The timing of pharmacological thromboprophylaxis initiation varies in clinical practice. In a meta-analysis of 39 studies on pharmacological thromboprophylaxis in cancer patients, 14 reported on DVT events and specified the timing of the first dose (preoperative versus post-operative). Preoperative administration of the first dose significantly reduced the DVT rate (RR 0.38, 95% CI 0.15-0.97), while post-operative administration of the first dose had no significant effect.14Guo Q. Huang B. Zhao J. et al.Perioperative Pharmacological Thromboprophylaxis in Patients With Cancer: A Systematic Review and Meta-analysis.Annals of Surgery. 2017; 265: 1087-1093Crossref PubMed Scopus (0) Google Scholar Two studies indicated a similar risk of bleeding between preoperative and post-operative commencement of pharmacological thromboprophylaxis: one RCT on 376 patients compared pre- versus post-operative UFH in colorectal cancer surgery, and one study compared a prospective cohort of 2058 surgical cancer patients receiving preoperative thromboprophylaxis with a matched historical cohort of patients receiving post-operative thromboprophylaxis.20Zaghiyan K.N. Sax H.C. Miraflor E. et al.Timing of Chemical Thromboprophylaxis and Deep Vein Thrombosis in Major Colorectal Surgery: A Randomized Clinical Trial.Annals of Surgery. 2016; 264: 632-639Crossref PubMed Scopus (0) Google Scholar,21Selby L.V. Sovel M. Sjoberg D.D. et al.Preoperative Chemoprophylaxis Is Safe in Major Oncology Operations and Effective at Preventing Venous Thromboembolism.J Am Coll Surg. 2016; 222: 129-137Crossref PubMed Google Scholar LMWH has a longer half-life (4-6 hours) compared with UFH (1-2 hours). To avoid bleeding, the interval between preoperative subcutaneous injection and surgical procedure should be generally longer in patients receiving LMWH, particularly when the highest approved prophylactic dose is used. Some LMWHs may only be licensed for post-operative commencement of VTE prophylaxis. Where different VTE prophylaxis doses are approved for a given LMWH, the highest dose is recommended to prevent VTE in cancer patients undergoing major surgery. A prospective, randomised, double-blind multicentre trial in patients undergoing surgery demonstrated in the group of cancer patients that prophylaxis with higher-dose dalteparin (5000 IU daily) compared with lower-dose dalteparin (2500 IU daily) reduced DVT rates from 14.9% to 8.5% (P < 0.001), without significant increase in bleeding complications.22Bergqvist D. Burmark U.S. Flordal P.A. et al.Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000 Xal units in 2070 patients.BJS (British Journal of Surgery). 1995; 82: 496-501Crossref Scopus (262) Google Scholar Perioperative prophylaxis with UFH tds is equally effective to LMWH od and superior to UFH twice daily (bd).16Matar C.F. Kahale L.A. Hakoum M.B. et al.Anticoagulation for perioperative thromboprophylaxis in people with cancer.Cochrane Database Syst Rev. 2018; 7: CD009447PubMed Google Scholar In a small RCT on 111 cancer patients undergoing oesophagectomy, the incidence of VTE was lower with nadroparin administered bd compared with od (0% versus 9.1%; P = 0.032).23Song J.-Q. Xuan L.-Z. Wu W. et al.Low molecular weight heparin once versus twice for thromboprophylaxis following esophagectomy: a randomised, double-blind and placebo-controlled trial.J Thorac Dis. 2015; 7: 1158-1164PubMed Google Scholar Nevertheless, more research is warranted to confirm these findings. The duration of post-operative thromboprophylaxis should be at least 10 days.24Bergqvist D. Agnelli G. Cohen A.T. et al.Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer.N Engl J Med. 2002; 346: 975-980Crossref PubMed Scopus (928) Google Scholar,25Rasmussen M.S. Jorgensen L.N. Wille-Jørgensen P. et al.Prolonged prophylaxis with dalteparin to prevent late thromboembolic complications in patients undergoing major abdominal surgery: a multicenter randomized open-label study.Journal of thrombosis and haemostasis : JTH. 2006; 4: 2384-2390Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The mean time from major surgery to VTE occurrence, however, is reported to be 17 days, and in over one-third of patients VTE occurs later than 21 days after surgery or hospital discharge.7Merkow R.P. Bilimoria K.Y. McCarter M.D. et al.Post-discharge venous thromboembolism after cancer surgery: extending the case for extended prophylaxis.Ann Surg. 2011; 254: 131-137Crossref PubMed Scopus (160) Google Scholar,26Agnelli G. Bolis G. Capussotti L. et al.A Clinical Outcome-Based Prospective Study on Venous Thromboembolism After Cancer Surgery: The @RISTOS Project.Annals of Surgery. 2006; 243: 89-95Crossref PubMed Scopus (0) Google Scholar These data support extended post-operative prophylaxis beyond 10 days in select patients. For example, several meta-analyses show that extended thromboprophylaxis with LMWH after major abdominal or pelvic cancer surgery reduces the risk of VTE compared with conventional duration of 2 weeks or less, without increasing the risk of major bleeding.14Guo Q. Huang B. Zhao J. et al.Perioperative Pharmacological Thromboprophylaxis in Patients With Cancer: A Systematic Review and Meta-analysis.Annals of Surgery. 2017; 265: 1087-1093Crossref PubMed Scopus (0) Google Scholar,27Carrier M. Altman A.D. Blais N. et al.Extended thromboprophylaxis with low-molecular weight heparin (LMWH) following abdominopelvic cancer surgery.The American Journal of Surgery. 2019; 218: 537-550Abstract Full Text Full Text PDF PubMed Google Scholar This effect is not limited to open surgery, but also occurs with laparoscopic surgery. In patients undergoing laparoscopic surgery for colorectal cancer, extended pharmacological prophylaxis for 4 weeks reduced VTE risk compared with prophylaxis for 1 week with similar bleeding rates.28Vedovati M.C. Becattini C. Rondelli F. et al.A Randomized Study on 1-Week Versus 4-Week Prophylaxis for Venous Thromboembolism After Laparoscopic Surgery for Colorectal Cancer.Annals of Surgery. 2014; 259: 665-669Crossref PubMed Scopus (132) Google Scholar Ambulatory patients. The risk of VTE is increased in patients with ‘active cancer’ (as defined in Supplementary Table S4).29Khorana A.A. Noble S. Lee A.Y.Y. et al.Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH.Journal of thrombosis and haemostasis : JTH. 2018; 16: 1891-1894Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar This risk is, however, very variable depending on individual factors (previous history of thrombosis, immobility, cardiovascular risk factors), the type and stage of cancer, the time since cancer diagnosis (within 6 months after first diagnosis and after progression or recurrence) and the use of systemic anticancer therapy30Falanga A. Russo L. Milesi V. et al.Mechanisms and risk factors of thrombosis in cancer.Critical reviews in oncology/hematology. 2017; 118: 79-83Crossref PubMed Scopus (0) Google Scholar; therefore, primary thromboprophylaxis is not justified in all of these patients. Identifying patients at high risk is of particular interest in this setting. RAMs and material for the calculation of the risk of CAT are provided in the Supplementary Material, Supplementary Tables S2 and S3 and Supplementary Figure S2, the latter of which exemplifies the inclusion of a biomarker of hypercoagulability (i.e. D-Dimer) to clinical predictors. Since thrombogenic potential varies depending on the type of cancer or the presence of certain oncogene mutations or rearrangements, the authors endorse the development of cancer-specific RAMs to further refine current risk stratification approaches or to develop new models that incorporate promising biomarkers. Results of these studies could alter the approach to risk stratification in the future. A recent meta-analysis and an individual patient-data meta-analysis including 10,431 ambulatory patients with cancer who participated in phase III RCTs, showed that prophylactic doses of heparins reduced symptomatic VTE by about 40% without increasing the bleeding risk as compared with no prophylaxis.31Rutjes A.W. Porreca E. Candeloro M. et al.Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.Cochrane Database Syst Rev. 2020; 12Cd008500PubMed Google Scholar,32Schünemann H.J. Ventresca M. Crowther M. et al.Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.Lancet Haematol. 2020; 7: e746-e755Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Two studies in pancreatic cancer using higher doses of LMWHs (150/IU/kg dalteparin or 1 mg/kg enoxaparin) for 3 months in patients receiving systemic anticancer treatment have shown a 85% and 65% RR reduction of any VTE and the composite of DVT and PE with number needed to treat (NNT) of 5 and 11, respectively.33Maraveyas A. Latest advances in preventing thromboembolic disease in the ambulatory oncology patient.Thrombosis research. 2020; 191: S91-S98Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar The recent AVERT and CASSINI studies randomised 574 and 841 patients, respectively, with intermediate-high risk of VTE [estimated thrombosis risk ≥9.6% over 6 months using the Khorana risk score [(KRS) ≥2] to either placebo or a factor Xa inhibitor for 6 months.34Carrier M. Abou-Nassar K. Mallick R. et al.Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.N Engl J Med. 2019; 380: 711-719Crossref PubMed Scopus (444) Google Scholar,35Khorana A.A. Soff G.A. Kakkar A.K. et al.Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.N Engl J Med. 2019; 380: 720-728Crossref PubMed Scopus (380) Google Scholar In the AVERT study, apixaban (2.5 mg bd) was associated with a lower rate of VTE [4.2% versus 10.2%; hazard ratio (HR) 0.41, 95% CI 0.26-0.65, NNT = 17] and a higher rate of major bleeding (3.5% versus 1.8%; HR 2.00, 95% CI 1.01-3.95; number needed to harm = 59).34Carrier M. Abou-Nassar K. Mallick R. et al.Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.N Engl J Med. 2019; 380: 711-719Crossref PubMed Scopus (444) Google Scholar In the CASSINI study, rivaroxaban (10 mg od) did not achieve significant VTE risk reduction over placebo (6.0% versus 8.8%; HR 0.66, 95% CI 0.4-1.09) with a major bleeding rate of 2% versus 1% (HR 1.96, 95% CI 0.59-6.49).35Khorana A.A. Soff G.A. Kakkar A.K. et al.Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.N Engl J Med. 2019; 380: 720-728Crossref PubMed Scopus (380) Google Scholar Neither study included patients with severe thrombocytopaenia (platelet count <50.000/mm3) or renal dysfunction [creatinine clearance (CrCl) <30 ml/min]. Shared decision making should take into account utility of oral route, renal and hepatic function, drug–drug interactions and risk of bleeding, with caution to be taken in patients with gastrointestinal malignancies, particularly if the primary lesion is luminal and non-resected. The duration of pharmacological thromboprophylaxis in ambulatory cancer patients cannot be firmly determined. The first three months from diagnosis and anticancer treatment initiation comprise the conventional higher-risk period during which >50% of VTE episodes occur, and all existing studies have covered at a minimum this period; the two DOAC studies34Carrier M. Abou-Nassar K. Mallick R. et al.Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.N Engl J Med. 2019; 380: 711-719Crossref PubMed Scopus (444) Google Scholar,35Khorana A.A. Soff G.A. Kakkar A.K. et al.Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.N Engl J Med. 2019; 380: 720-728Crossref PubMed Scopus (380) Google Scholar had a predetermined, 6-month thromboprophylaxis period and the two pancreatic ductal adenocarcinoma studies33Maraveyas A. Latest advances in preventing thromboembolic disease in the ambulatory oncology patient.Thrombosis research. 2020; 191: S91-S98Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar explored a maximum of 3 months at a higher dose of LMWH. These patients, however, also have a KRS of ≥2 points and very often progressive disease; hence, prolonging thromboprophylaxis with a DOAC up to 6 months remains evidence-based. For thromboprophylaxis beyond 6 months an individualised approach should be considered. LMWHs represent the agents of choice for VTE thromboprophylaxis in patients with cancer hospitalised for an acute medical illness. The recommendation of pharmacological thromboprophylaxis to prevent VTE for inpatients with cancer is based on the results from large clinical trials of hospitalised medical patients.36Samama M.M. Kleber F.X. An update on prevention of venous thromboembolism in hospitalized a