- Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important cause of morbidity and mortality among patients with cancer.
- Patients with cancer are significantly more likely to develop VTE than people without cancer and experience higher rates of VTE recurrence and bleeding complications during VTE treatment.
- Comprehensive management of VTE in patients with cancer includes both the identification of patients who are most likely to benefit from pharmacologic prophylaxis, as well as effective treatment to reduce the risk of VTE recurrence and mortality.
- 1.1. Hospitalized patients who have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. (Moderate Recommendation; EB-I)
- 1.2. Hospitalized patients who have active malignancy without additional risk factors may be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. (Moderate Recommendation; EB-L)
- 1.3. Routine pharmacologic thromboprophylaxis should not be offered to patients admitted for the sole purpose of minor procedures or chemotherapy infusion, nor to patients undergoing stem-cell/bone marrow transplantation. (Moderate Recommendation; IC-Ins)
- 2.1. Routine pharmacologic thromboprophylaxis should not be offered to all cancer outpatients. (Strong Recommendation; EB-I/H)
- 2.2. High-risk outpatients with cancer (Khorana score [Table 2] ≥2 prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban or low-molecular-weight heparin (LMWH) provided there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting. (Moderate Recommendation; EB-I/H for apixaban and rivaroxaban I for LMWH)
- 2.3. Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients. (Strong Recommendation; EB-I)
- 3.1. All patients with malignant disease undergoing major surgical intervention should be offered pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or LMWH unless contraindicated because of active bleeding, or high bleeding risk, or other contraindications. (Strong Recommendation; EB-H)
- 3.2. Prophylaxis should be commenced preoperatively. (Moderate Recommendation; EB-I)
- 3.3. Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk. (Strong Recommendation; EB-I)
- 3.4. A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients. (Moderate Recommendation; EB-I)
- 3.5. Pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7–10 days. Extended prophylaxis with LMWH for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features such as restricted mobility, obesity, history of VTE, or with additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis. (Strong Recommendation; EB-H)
- 4.1. Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5–10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance <30 mL/min). (Strong Recommendation; EB-H)
- 4.2. For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists (VKA). VKA are inferior but may be utilized if LMWH or direct oral anticoagulants (DOAC) are not accessible. There is an increase in major bleeding risk with DOAC, particularly observed in GI and potentially GU malignancies. Caution with DOAC is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOAC. (Strong Recommendation; EB-H)
- 4.3. Anticoagulation with LMWH, DOAC, or VKA beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile (Weak to Moderate Recommendation; IC-L)
- 4.4. Based on expert opinion in the absence of randomized trial data, uncertain short-term benefit, and mounting evidence of long-term harm from filters, the insertion of a vena cava filter should not be offered to patients with established or chronic thrombosis (VTE diagnosis more than 4 weeks ago) nor to patients with temporary contraindications to anticoagulant therapy (e.g., surgery). There also is no role for filter insertion for primary prevention or prophylaxis of PE or DVT due to its long-term harm concerns. It may be offered to patients with absolute contraindications to anticoagulant therapy in the acute treatment setting (VTE diagnosis within the past 4 weeks) if the thrombus burden was considered life-threatening. Further research is needed. (Moderate Recommendation; IC-L/I)
- 4.5. The insertion of a vena cava filter may be offered as an adjunct to anticoagulation in patients with progression of thrombosis (recurrent VTE or extension of existing thrombus) despite optimal anticoagulant therapy. (Weak Recommendation; IC-L/I)
- This is based on the panel’s expert opinion, given the absence of a survival improvement, a limited short-term benefit, but mounting evidence of the long-term increased risk for VTE.
- 4.6. For patients with primary or metastatic central nervous system malignancies and established VTE, anticoagulation as described for other patients with cancer should be offered, although uncertainties remain about choice of agents and selection of patients most likely to benefit. (Moderate Recommendation; IC-L)
- 4.7. Incidental pulmonary embolism and deep vein thrombosis should be treated in the same manner as symptomatic VTE, given their similar clinical outcomes compared to cancer patients with symptomatic events. (Moderate Recommendation; IC-L)
- 4.8. Treatment of isolated subsegmental pulmonary embolism or splanchnic or visceral vein thrombi diagnosed incidentally should be offered on a case-by-case basis, considering potential benefits and risks of anticoagulation. (Moderate Recommendation; IC-Ins)
- 5. Anticoagulant use is not recommended to improve survival in patients with cancer without VTE. (Strong Recommendation; EB-H)
- 6.1. There is substantial variation in risk of VTE between individual cancer patients and cancer settings. Patients with cancer should be assessed for VTE risk initially and periodically thereafter, particularly when starting systemic antineoplastic therapy or at the time of hospitalization. Individual risk factors, including biomarkers or cancer site, do not reliably identify patients with cancer at high risk of VTE. In the ambulatory setting among patients with solid tumors treated with systemic therapy, risk assessment can be conducted based on a validated risk assessment tool (Khorana score, Table 2). (Strong Recommendation; EB-I)
- 6.2. Oncologists and members of the oncology team should educate patients regarding VTE, particularly in settings that increase risk such as major surgery, hospitalization, and while receiving systemic antineoplastic therapy. (Strong Recommendation; IC-Ins)
Notes regarding off-label use in guideline recommendations: apixaban, rivaroxaban, and LMWH have not been FDA approved for thromboprophylaxis in outpatients with cancer (2.2 for apixaban and rivaroxaban; recommendations 2.2 and 2.3 for LMWH). Dalteparin is the only LMWH with FDA approval for extended therapy to prevent recurrent thrombosis in patients with cancer (4.2).
Table 1. Contraindications to Therapeutic Anticoagulant in Patients with Cancera
|Non-DOAC Anticoagulants and DOAC Anticoagulants:|
|Non-DOAC Anticoagulants and DOAC Anticoagulants:|
|Patients for whom Anticoagulation is of Uncertain Benefit|
|Patient Characteristics and Values|
b Absolute contraindications are situations in which anticoagulation should not be given because the risk of harm associated with bleeding is very likely to exceed the potential benefit from anticoagulation.
c Relative contraindications are situations in which anticoagulation may be given if the risk of recurrent or progressive thrombosis is estimated to exceed the risk of bleeding. Due to DOACs’ increased risk for major bleeding events compared to LMWHs in the VTE treatment setting, LMWHs are generally the preferred agents in settings with an increased bleeding risk, especially in settings of relative contraindications. Patient preferences also need to be taken into consideration when making anticoagulation choices.
d There is limited evidence regarding the safety of DOAC use in this setting.
e The panel was not unanimous in the decision to list these as relative contraindications for DOAC, since we do not have adequate safety data in these clinical settings. Given the known increased risk in major and clinically-relevant non-major bleeding for DOAC compared to LMWH in the VTE treatment setting, these relative contraindications for non-DOAC anticoagulants may be considered absolute contraindications for DOAC use in some patients.
Additional potential contraindications exist for DOAC including: non-healed surgical site in the perioperative period, trauma conferring a high bleeding risk, minor hemorrhagic malignant or non-malignant lesions, treated brain metastases, other central nervous system malignancies, the use of cyberknife, presence of lesser drug-drug interactions potentially impacting drug efficacy or safety, anticipated nausea or vomiting impacting oral DOAC intake, obesity (body mass index [BMI] >40 or a weight of >120 kg).
Table 2. Predictive Model for Chemotherapy-associated VTE in the Ambulatory Setting
|Site of cancer|
|Very high risk (stomach, pancreas)||2|
|High risk (lung, lymphoma, gynecologic, bladder, testicular, renal)||1|
|Pre-chemotherapy platelet count ≥350,000/µL||1|
|Hemoglobin level <10g/dL or use of red cell growth factors||1|
|Pre-chemotherapy leukocyte count >11,000/µL||1|
|Body mass index ≥35 kg/m2||1|
|Calculate Total Score, adding points for each criterion in the model|
High-risk score ≥3 points
Intermediate risk score = 1–2 points
Low-risk score = 0 points
Table 3. Dosing Regimens for Prophylaxis/Treatment of VTE in Patients with Cancer
|Pharmacologic (Anticoagulant) Prophylaxis|
|Hospitalized medical patientsb||Unfractionated heparin||5,000 U q8hc|
|Dalteparin||5,000 U qd|
|Enoxaparin||40 mg qd|
|Fondaparinuxd||2.5 mg qd|
|Surgical patientsb||Unfractionated heparin||5,000 U 2–4 h pre-op and q8hc thereaftere|
|Dalteparin||2,500 U 2–4 h pre-ope and 5,000 U qd thereafter,f OR 5,000 U 2–4 h pre-ope or 10–12 h pre-op and 5,000 U qd thereafterf|
|Enoxaparin||40 mg 2–4 h pre-ope or 10–12 hr pre-op and 40 mg qd thereafterf|
|Fondaparinuxd||2.5 mg qd beginning 6–8h post-op|
|Outpatientsb||Dalteparind,g||5,000 U qd|
|Enoxaparind,g||40 mg qd|
|Fondaparinuxd,h||2.5 mg qd|
|Apixaband||2.5 mg orally, twice daily|
|Rivaroxaband||10 mg orally, once daily|
|Treatment of established VTEi|
|Initial||Unfractionated heparin (UFH)j||80 U/kg IV bolus, then 18 U/kg/h IV and adjust dose based on aPTTk|
|Dalteparinj,l,m||100 U/kg q12h|
|200 U/kg qd|
|Enoxaparinj,l,m,n||1 mg/kg q12h|
|1.5 mg/kg qd|
|Tinzaparinj,l,m,o||175 U/kg qd|
|Fondaparinuxj,l,p||<50 kg: 5.0 mg qd|
50–100 kg: 7.5 mg qd
100 kg: 10 mg qd
|Rivaroxaban||15 mg orally q12h for 21 days|
|Long-termp,q,r||Dalteparinl,m,s||200 U/kg qd for 1 month, then 150 U/kg qd|
|Enoxaparinl,m,n||1.5 mg/kg qd|
|1 mg/kg q12h|
|Tinzaparinm,o||175 U/kg qd|
|Warfarin||Adjust dose to maintain INR 2-3|
|Rivaroxabanm,t||15 mg orally q12h for 21 days, followed by: 20 mg qd thereafter (both doses with food)|
|Edoxabanm,t||Needs ≥5 days of parenteral anticoagulation prior to its start, then switch to: 60 mg orally qd or 30 mg orally qd in those weighing ≤60 kg, have creatinine clearance between 30–50 mL/min or need con-comitant use of a P-gp inhibitor|
b Duration for medical patients is for the length of hospital stay or until fully ambulatory; for surgical patients, prophylaxis should be continued for ≥7–10 days. Extended prophylaxis for ≤4 weeks should be considered for high-risk patients. Duration for outpatient prophylaxis is somewhat uncertain, since most studies did not assess beyond 6 months.
c Unfractionated heparin 5,000 U every 12 hours has also been used in moderate-risk cancer but appears to be less effective, particularly in oncologic surgery.
d This drug is not approved by the U.S. Food and Drug Administration for this indication.
e UFH: The first prophylactic UFH dose should be administered no sooner than 1h after needle/catheter placement. In patients receiving preoperative prophylactic low dose UFH, neuraxial puncture/catheter manipulation or removal should not occur within the first 4–6h after UFH administration. Subsequent UFH administration may occur no earlier than 1h after catheter removal. In patients receiving preoperative therapeutic UFH (>15,000 U/24h), neuraxial block/catheter removal or manipulation should not occur within 12 h after UFH administration.
LMWH: The first prophylactic LMWH dose should be administered no sooner than 4h after needle/catheter placement. In patients receiving preoperative prophylactic LMWH doses, neuraxial puncture/catheter manipulation or removal should not occur within the first 12 h after LMWH administration. Subsequent LMWH administration may occur no earlier than 4h after catheter removal. In patients receiving preoperative therapeutic LMWH doses, neuraxial block/catheter removal or manipulation should not occur within 24 h after heparin administration.
Clinicians should refer to their institutional guidelines and/or the American Society of Regional Anesthesia Guidelines for more detailed information about LMWH and other agents.
f Clinicians should follow the regimens for the initiation and dosing of preoperative LMWH approved by regulatory agencies, as shown in the package insert.
g Higher prophylactic doses were used for pancreatic cancer patients: dalteparin 200 IU/kg once daily for 4 weeks followed by a stepdown to 150 IU/kg for a further 8 weeks in FRAGEM and enoxaparin 1 mg/kg once daily in CONKO-004.
h Fondaparinux has not been studied in the outpatient prophylaxis setting. It should be considered only if the patient has contraindications for other LMWH and DOAC use is considered an inferior option.
i Contraindications to therapeutic anticoagulation are listed in Table 1.
j Parenteral anticoagulants should overlap with warfarin for 5–7 days minimum and should be continued until the INR is in the therapeutic range for 2 consecutive days.
k Unfractionated heparin infusion rate should be adjusted to maintain the aPTT within the therapeutic range in accordance with local protocols to correspond with a heparin level of 0.3–0.7 U/mL using a chromogenic anti-factor Xa assay.
l Dependent on significant renal clearance, avoid in patients with creatinine clearance ≤30 mL/min or adjust dose based on anti-factor Xa levels.
m Optimal dose unclear in patients >120 kg.
n Twice daily dosing may be more efficacious than once daily dosing for enoxaparin based on post-hoc data.
o This drug is not available in the U.S.
p Fondaparinux had a higher rate of recurrent thrombosis and no difference in bleeding compared with enoxaparin in cancer patients in a post-hoc, subgroup analysis. It is not a standard option, but may be used for long-term anticoagulation if standard LMWH or DOAC are not feasible options for the patient. Dosing for long term treatment with fondaparinux is the same as for initial treatment. (Fondaparinux Prescribing Information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021345s035lbl.pdf).
q Total duration of therapy depends on clinical circumstances. See full text guideline for more detailed discussion.
r Apixaban and dabigatran do not have fully published results from cancer-specific clinical trials. Prospective randomized trial data in cancer patients with active disease on cancer therapy are needed prior to their use. Therefore, they are currently not recommended for routine use in cancer patients with active disease.
s This is the only LMWH with FDA approval for extended therapy to prevent recurrent thrombosis in cancer patients.
t Edoxaban has the highest level of evidence for cancer patients among all the DOAC, followed by rivaroxaban. Limited data from small, unpublished patient series suggest that the efficacy of DOAC in patients with a weight above 120 kg might be reasonable based on anti-Xa levels. The data are very limited however, and LMWH are likely still preferred in this setting. Please refer to the package inserts for detailed information regarding potential dosing adjustment needs, especially regarding renal impairment, liver failure, weight extremes, or drug-drug interaction.