Table 5.

Guideline recommendations for treatment of cancer‐associated VTE

Guideline	Recommendations
American Society of Clinical Oncology 2020	Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban. Among parenteral agents, LMWH preferred over UFH in the absence of severe renal impairment (CrCl <30 mL/min). (Recommendation type: evidence based; evidence quality: high; strength of recommendation: strong.) For long‐term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months is preferred over VKA. VKAs are inferior but may be used if LMWH or DOACs are not accessible. DOACs are associated with increased major bleeding in GI and potentially GU malignancies. Caution with DOACs is warranted in other settings with high risk for mucosal bleeding. Drug‐drug interactions should be checked before use of DOACs. (Recommendation type: evidence based; evidence quality: high; strength of recommendation: strong.) Anticoagulation beyond the initial 6 months should be offered to select patients with active cancer—including metastatic disease or those receiving chemotherapy—and needs to be reassessed on an intermittent basis to ensure a continued favorable risk‐benefit profile. (Recommendation type: informal consensus; evidence quality: low; Strength of recommendation: weak to moderate.) The insertion of an IVC filter should not be offered to patients with established or chronic thrombosis (VTE diagnosis >4 weeks) or to patients with a temporary contraindication to anticoagulation. There is no role for IVC filters for primary prevention of VTE, but they may be offered to patients with absolute contraindications to anticoagulation in the acute setting if thrombus burden is considered life‐threatening. (Recommendation type: informal consensus; evidence quality: low to intermediate; strength of recommendation: moderate.) An IVC filter may be offered as an adjunct to anticoagulation in patients with progressive thrombosis despite optimal anticoagulation. (Recommendation type: informal consensus; evidence quality: low to intermediate; strength of recommendation: weak.) For patients with primary or metastatic CNS malignancies and VTE, anticoagulation should be offered, although uncertainty remains as to choice of agent and the type of patients most likely to benefit. (Recommendation type: informal consensus; evidence quality: low; strength of recommendation: moderate.) Incidental VTE should be treated in the same manner as symptomatic VTE. (Recommendation type: informal consensus; evidence quality: low; strength of recommendation: moderate.) Treatment of isolated subsegmental PE or splanchnic or visceral vein thrombi should be offered on a case‐by‐case basis considering the potential benefits and risks. (Recommendation type: informal consensus; evidence quality: insufficient; strength of recommendation: moderate.)
International Society of Thrombosis and Hemostasis 2018	Recommend individualized treatment regimens after shared decision making with patients. Suggest edoxaban and rivaroxaban for patients with cancer with acute VTE, a low risk of bleeding, and no drug‐drug interactions. LMWHs are an acceptable alternative. Suggest LMWH for patients with acute VTE at high risk for bleeding, including those with luminal GI malignancy with intact primaries, GU malignancies, nephrostomy tubes, or GI mucosal abnormalities. Edoxaban and rivaroxaban are acceptable alternatives if no drug‐drug interactions.
International Initiative on Thrombosis and Cancer 2019	LMWH is recommended over UFH for initial treatment unless CrCl <30 mL/min (grade 1B). Values and preferences: LMWH is easier to use than UFH. A once‐daily LMWH regimen is recommended unless patient characteristics (fragile patients at increased bleeding risk) require a twice‐daily regimen. Rivaroxaban or edoxaban (after initial LMWH/UFH for 5 days) can be used for initial treatment if CrCl ≥30 mL/min and patient is not at high risk of GI or GU bleeding (grade 1B). UFH can be used for initial treatment when LMWH or DOACs are contraindicated or not available (grade 2C). Fondaparinux can also be used for initial treatment if CrCl ≥30 mL/min (grade 2D). Values and preferences: Fondaparinux is easier to use than UFH. Thrombolysis can only be considered on a case‐by‐case basis with specific attention paid to contraindications, especially bleeding. (Guidance based on evidence of very low quality and high bleeding risk.) Values and preferences: Expert opinion is recommended prior to thrombolysis, and it should only be done in centers with the appropriate expertise. IVC filters may be considered for initial treatment when anticoagulation is contraindicated or when PE occurs despite optimal anticoagulation. Periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe. (Guidance based on evidence of very low quality and unknown balance of risk and benefits.) LMWH favored over VKA for early maintenance and long‐term therapy if CrCl ≥30 mL/min (grade 1A). Values and preferences: Daily injections can be a burden to patients. Rivaroxaban and edoxaban recommended for patients with CrCl ≥30 mL/min if no impairment in GI absorption or strong drug‐drug interactions (grade 1A). Use caution in patients with GI malignancies. LMWH or DOACs should be continued for at least 6 months (grade 1A). After 6 months, continuation of therapy should be based on individual assessment of benefit‐risk ratio, tolerability, drug availability, patient preference, and cancer activity. (Guidance in the absence of data.) In the event of recurrent VTE, three options can be considered: (a) increase LMWH by 20%–25% or switch to DOAC; (b) for DOACs, switch to LMWH; and (c) for VKAs, switch to LMWH or DOAC. (Guidance based on evidence of very low quality and unknown balance of desirable and undesirable effects.) Effect of therapy should be monitored for symptomatic improvement.
National Comprehensive Cancer Network 2020	Apixaban (category 1), edoxaban after at least 5 days of parenteral anticoagulation (category 1), or rivaroxaban (category 2A) preferred over LMWH for patients without GI malignancies. LMWH (dalteparin category 1) preferred over DOACs in patients with GI malignancies. Dabigatran after at least 5 days of parenteral anticoagulation (alternative to apixaban, edoxaban, rivaroxaban, or LMWH if not appropriate or unavailable) (category 2A). UFH is an alternative to LMWH for initial therapy (category 2B) and is preferred for patients with CrCl <30 mL/min. Fondaparinux is contraindicated in patients with CrCl <30 mL/min and should be used with caution with CrCl 30–50 mL/min. Dabigatran, edoxaban, and rivaroxaban are contraindicated with CrCl <30 mL/min. Apixaban is contraindicated if CrCl <25 mL/min. Apixaban and edoxaban are contraindicated in patients with clinically significant liver disease (total bilirubin >1.5 × ULN or transaminases >2 × ULN). Dabigatran and rivaroxaban are contraindicated if transaminases >3 × ULN. Apixaban and rivaroxaban should not be used in conjunction with strong inducers/inhibitors of CYP3A4 and P‐glycoprotein. Dabigatran and edoxaban should not be used in conjunction with strong inducers/inhibitors of P‐glycoprotein. Choice of anticoagulation regimen should be based on individual risk of thrombosis and bleeding, renal and hepatic function, inpatient/outpatient status, FDA approval status, ease of administration, cost, burden of laboratory monitoring, agent reversibility, and patient preferences. Consider catheter‐directed pharmacomechanical thrombolysis for DVT in patients at low risk for bleeding but at risk for limb loss or severe persistent symptoms despite anticoagulation (category 2A). Consider systemic or catheter‐directed thrombolysis (category 2A) or embolectomy (category 2B) for patients with hemodynamically unstable PE at low risk for bleeding. Consider IVC filter (retrievable preferred) if anticoagulation is contraindicated for acute VTE (within 1 month of diagnosis). Recommend filter retrieval once patient is tolerating anticoagulation (category 2A). Incidental PE should be treated similarly to symptomatic PE (category 2A). Recommended duration of anticoagulation therapy is for as long as the patient's cancer is active or under treatment. Providers should continue to discuss the risks and benefits (category 2A). For recurrent VTE on UFH, recommend considering HIT, antiphospholipid syndrome (check UFH anti‐Xa level), increase dose of UFH, or switch to LMWH or DOAC (category 2B). For recurrent VTE on LMWH, recommend considering HIT, switch to twice‐daily injections or increase dose or switch to fondaparinux or DOAC (category 2B). For recurrent VTE on fondaparinux, recommend considering HIT or switching to UFH, LMWH, or DOAC (category 2B). For recurrent VTE on warfarin, recommend switching to LMWH, UFH, fondaparinux, or DOAC (category 2B). For recurrent VTE on DOAC, recommend switching to LMWH or fondaparinux (category 2B).
Spanish Society of Medical Oncology 2018	LMWH is the drug of choice for initial treatment of VTE (grade 1B). Rivaroxaban can be used if bleeding risk is low and no significant drug‐drug interactions (grade 1B). UFH and fondaparinux can be considered as alternative agents for initial treatment (grade 1B). LMWH and DOACs for 6 months are drugs of choice for long‐term treatment of VTE. DOACs must be used in patients with low bleeding risk and no significant drug‐drug interactions (grade 1A). Extended‐duration treatment should be considered in high‐risk patients such as those with active cancer and those receiving systemic therapy. Patients should be reevaluated frequently to assess risk‐benefit ratio of continued anticoagulation (grade 2C). Incidental VTE should be treated similarly to symptomatic VTE (grade 1B). Treatment of isolated incidental subsegmental PE or superficial vein thrombosis should be individualized. It is suggested to consider anticoagulation (grade 2C). Therapeutic LMWH should be used for recurrent VTE in patients on VKA or prophylactic or intermediate doses of LMWH (grade 2B). For recurrent VTE on therapeutic LMWH, increase LMWH dose 25% or switch to DOAC (grade 2B). For recurrent VTE on DOAC, switch to LMWH or increase DOAC dose to therapeutic dose if subtherapeutic doses were being used (grade 3C). IVC filter insertion may be considered if anticoagulation contraindicated or recurrent events occur despite appropriate anticoagulation. A retrievable filter is preferred, and anticoagulation should be resumed as soon as possible (grade 2B).

Abbreviations: CNS, central nervous system; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; GU, genitourinary; HIT, heparin‐induced thrombocytopenia; IVC, inferior vena cava; LMWH, low‐molecular‐weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin; ULN, upper limit of normal range; VKA, vitamin K antagonist; VTE, venous thromboembolism.