VTE guidelines

Traditionally, anticoagulants used to treat signs and symptoms of VTE have included LMWH or vitamin K antagonists (VKAs). More recently, DOACs, have emerged as a potential option for pharmacologic thromboprophylaxis and for treatment of patients with cancer at risk or at high risk of VTE¹. Listen to Professor Agnelli from the University of Perugia discuss the current unmet needs in treating CAT.

EHRA, ISTH, and NCCN have recently incorporated DOACs into their recommendations².

A number of guidelines which address anticoagulation in patients with cancer have been published by agencies such as the European Heart Rhythm Association (EHRA 2019), International Initiative on Thrombosis and Cancer (ITAC-CME 2016), American Society of Clinical Oncology (ASCO-2019), American College of Chest Physicians (ACCP 2016), International Society of Thrombosis and Hemostasis (ISTH 2019), and the National Comprehensive Cancer Network (NCCN 2018). Most of these guidelines have focused on the use of heparin and LMWH. However, EHRA, ISTH, and NCCN have recently incorporated DOACs into their recommendations. A more unified approach is required to assist clinicians to choose the appropriate DOACs and the optimal dosage and duration of therapy².

Historically, treatment with LMWH followed by VKA for venous thromboembolic diseases including deep vein thrombosis (DVT) and pulmonary embolism (PE) was associated with low adherence and major bleedings rates. The landmark CANTHANOX, ONCENOX, CLOT, LITE, and CATCH trials demonstrated that LMWH's were superior in preventing recurrent VTE in cancer patients with similar or improved bleeding profiles compared to VKAs^3–8. ACCP Guidelines issued in 2016 recommend LMWH over VKA for the management of VTE, but patients with cancer often do not tolerate daily injections for extended periods of time, resulting in poor compliance and increased recurrence rates. The cost associated with LMWH treatment are substantially higher than with DOACs; for example, in the US in 2019, these costs were approximately $19,337 and $6,239, respectively over 12 months^2,9.

The most recent ASCO, ISTH, and NCCN guideline updates recommend LMWH for at least six months because of its improved efficacy over VKAs. Anticoagulation with LMWH or VKAs beyond the initial six months may be considered for select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy¹⁰.

Table 1. The recommended ASCO dosing schedule (adapted from Key et al, 2020¹¹).

European Society for Medical Oncology (ESMO) guidelines also recommended long-term anticoagulant treatment in cancer patients for six months, stating that 75–80% (ie. 150 U/kg once daily) of the initial dose of LMWH is safe and more effective than treatment with a VKA¹⁰.

Although the NCCN recommend LMWH as monotherapy (without warfarin) for the first six months of chronic treatment of proximal DVT or PE (and for prevention of recurrent VTE in patients with advanced or metastatic cancer who do not have contraindications to anticoagulation), the decision to continue LMWH beyond this time frame or to switch to warfarin therapy for patients requiring longer durations of anticoagulation therapy should be based on clinical judgment¹⁰.

While data remains limited and evolving, DOACs appear to offer several benefits, including ease of administration and similar efficacy compared to LMWH in preventing recurrent VTE in cancer patients. Additional studies are underway to evaluate the role of DOACs compared to LMWH in the setting of cancer¹.

Anticoagulants recommended by NCCN and ASCO for treatment of cancer-associated VTE include LMWH, unfractionated heparin, VKA, and DOACs. Currently available DOACs include factor Xa inhibitors (apixaban, rivaroxaban, betrixaban, and edoxaban) and a direct thrombin inhibitor (dabigatran)¹.

Oral factor Xa inhibitors function by targeting the prothrombin binding site on factor Xa, thus blocking the conversion of prothrombin to thrombin. Meanwhile, the direct thrombin inhibitor functions as a direct competitive inhibitor of both free- and clot-bound thrombin and binds to the active site of thrombin, inhibiting the conversion of fibrinogen to fibrin. Specific FDA indications for use vary by the agent selected, but DOACs are established in risk reduction of stroke and systemic embolism in patients with non-valvular atrial fibrillation and for the prevention and/or treatment of VTE in certain settings. A meta-analysis including six phase III clinical trials comparing DOACs with VKAs for the therapeutic anticoagulation treatment of the disease in the general population found that treatment of VTE with a DOAC significantly reduced the risk of bleeding and clinically relevant non-major bleeding compared to VKAs. Overall, both had similar efficacy in the treatment of the disease and given their ease of administration, lack of routine testing required, and efficacy, DOACs have emerged as an appealing option for the prevention and treatment of VTE in patients with cancer^1,12.

LMWH has remained the standard treatment for cancer-associated VTE. However, with the increased use of DOACs, three recent randomised controlled trials have been conducted to compare the safety and efficacy of DOACs with LMWH³. The results of these trials have informed recommendations from evidence-based society guidelines issued in 2016 by the ACCP, in 2020 by ASCO, in 2020 by the NCCN, in 2020 by the ISTH, and in 2019 by the European Cardiology Society/European Respiratory Society (ESC/ERS)^11,13–18 Listen to Professor Agnelli for more insight into whether there is sufficient efficacy data to support the use DOACs for the treatment of CAT.

DOAC Evidence in Cancer-Associated VTE

The Hokusai VTE Cancer trial, the Select-D trial and the ADAM-VTE trial compared the efficacy and safety of DOACs with LMWH (Table 2).

Table 2. Direct oral anticoagulant (DOAC) for VTE prophylaxis and treatment in patients with cancer (adapted from Ramacciotti et al, 2019²). Data from prospective randomized trials. CAT, cancer-associated thrombosis; CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; NR, non-representative; VTE, venous thromboembolism.

The Hokusai VTE Cancer trial was a randomised, open-label, noninferiority trial of the LMWH dalteparin versus the DOAC edoxaban. All patients received dalteparin for at least 5 days and at randomisation, patients continued on LMWH or transitioned to the DOAC. The dalteparin dose was 200 IU/kg daily for 1 month, followed by dalteparin 150 IU/kg daily; the edoxaban dose was 60 mg/d. Treatment was given for at least 6 months and up to 12 months. The results of this study showed that edoxaban was noninferior to dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin¹⁹.

The hazard ratios for the composite end point were very similar although there was a suggestion of greater efficacy with edoxaban, but with the consequence of a higher rate of major bleeding, mainly due to upper gastrointestinal (GI) bleeds in patients with primary GI cancers. These findings speak to the need for proper patient selection²⁰.

In the Select-D trial, a randomised, open-label, pilot trial, the LMWH dalteparin was compared with the DOAC rivaroxaban. The dalteparin dose was 200 IU/kg daily for 1 month, followed by dalteparin 150 IU/kg daily for months 2 to 6; the rivaroxaban dose was 15 mg twice daily for 3 weeks, followed by rivaroxaban 20 mg daily for 6 months. Results of this pilot study showed that was associated with relatively low VTE recurrence but higher rates of clinically relevant and major bleeding. These tended to correlate with upper GI cancers^19,21.

The ADAM-VTE trial was also an open-label trial that randomised 300 cancer patients with acute VTE to receive apixaban (10mg twice daily for 7 days then 5mg twice daily) or dalteparin (200 IU/kg daily for 1 month followed by 150 IU/kg daily) for 6 months. Patients with Eastern Cooperative Oncology Group (ECOG) performance (a scale describing a patient’s level of functioning in terms of ability to care for themselves, daily activity, and physical ability) <2 were excluded. Metastatic disease was present in approximately 66% of patients in both arms and nearly 74% in each arm were receiving concurrent cancer treatment. Major bleeding occurred in none of 145 patients receiving apixaban compared with 1.4% of 142 patients receiving dalteparin. Recurrent VTE occurred in 0.7% of apixaban compared to 6.3% of dalteparin patients. Major bleeding or clinically relevant non-major bleeding was 6% for both groups. Overall, oral apixaban was associated with low major bleeding and VTE recurrence rates for the treatment of VTE in cancer patients^3,19,22. 

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 the effective treatment to reduce the risk of VTE recurrence and mortality.

DOACs are now endorsed by the most recent ASCO, ACCP, ISTH, ESC/ERS and NCCN guidelines as options for VTE prophylaxis and treatment in selected cohorts^{11,13–18,22,23}.  DOACs are also recommended during the early maintenance period (up to 6 months) and in the long-term (beyond 6 months) for patients with cancer when creatinine clearance is ≥30 mL/min and in the absence of strong drug–drug interactions or GI absorption impairment²³.

DOAC Treatments for CAT

Most hospitalised patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalisation. Thromboprophylaxis is not routinely recommended for all outpatients with cancer¹¹. The overall consensus among multiple international treatment guidelines from the ACCP, ASCO, ITAC-CME, NCCN, and ESMO is that that prophylaxis should be with LMWH or unfractionated heparin for primary prevention of VTE in patients with cancer undergoing surgery. Learn more about the challenges of thromboprophylaxis and whether patients could benefit from it by listening to this discussion with Professor Agnelli.

So, should patients with cancer that have been hospitalised receive anticoagulation for VTE prophylaxis¹¹? The ASCO 2019 guidelines recommend that patients who have been hospitalised and have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications. 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 transplantation¹¹.

On the question of whether ambulatory patients with cancer should receive anticoagulation for VTE prophylaxis during systemic chemotherapy? The ASCO 2019 guideline recommendations are that routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer. High-risk outpatients with cancer (Khorana score ³2 prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or 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 setting¹¹.

Treatment

What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? According to the ASCO 2019 guideline updates initial anticoagulation may involve LMWH, unfractionated heparin (UFH), fondaparinux, or rivaroxaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5 to 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)¹¹.

For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over VKAs. VKAs are inferior but may be used if LMWH or DOACs are not accessible. There is an increase in major bleeding risk with DOACs, particularly observed in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interactions should be checked prior to using a DOAC¹¹.

Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to selected groups of 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 favourable risk-benefit profile¹¹.

Based on expert opinion in the absence of randomised 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 long term safety 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-threatening¹¹.

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. 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 VTE¹¹.

For patients with primary or metastatic central nervous system (CNS) 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. Incidental PE and deep vein thrombosis should be treated in the same manner as symptomatic VTE, given their similar clinical outcomes compared with patients with cancer with symptomatic events¹¹.

Treatment of isolated subsegmental PE or splanchnic or visceral vein thrombi diagnosed incidentally should be offered on a case-by-case basis, considering potential benefits and risks of anticoagulation¹¹.

Table 3. Dosing regimens for prophylaxis/treatment of VTE in patients with cancer (adapted from Key et al, 2020¹¹). aPTT, activated partial thromboplastin time; INR, international normalised ratio; IV, intravenous; UFH, unfractionated heparin; VTE, venous thromboembolism

^aUFH 5,000 U every 12 hours has also been used in moderate-risk cancer but appears to be less effective, particularly in oncologic surgery. ^bThis drug is not approved by the US Food and Drug Administration for this indication. ^cUFH: The first prophylactic UFH dose should be administered no sooner than 1 hour after needle/catheter placement. In patients receiving preoperative prophylactic low-dose UFH, neuraxial puncture/catheter manipulation or removal should not occur within the first 4-6 hours after UFH administration. Subsequent UFH administration may occur no earlier than 1 hour after catheter removal. In patients receiving preoperative therapeutic UFH (. 15,000 U/24 hours), neuraxial block/catheter removal or manipulation should not occur within 12 hours after UFH administration. LMWH: The first prophylactic LMWH dose should be administered no sooner than 4 hours after needle/catheter placement. In patients receiving preoperative prophylactic LMWH doses, neuraxial puncture/catheter manipulation or removal should not occur within the first 12 hours after LMWH administration. Subsequent LMWH administration may occur no earlier than 4 hours after catheter removal. In patients receiving preoperative therapeutic LMWH doses, neuraxial block/catheter removal or manipulation should not occur within 24 hours after heparin administration. Clinicians should refer to their institutional guidelines and/or the American Society of Regional Anaesthesia Guidelines for more detailed information about LMWH and other agents. ^dClinicians should follow the regimens for the initiation and dosing of preoperative LMWH approved by regulatory agencies, as shown in the package insert. ^eHigher prophylactic doses were used for patients with pancreatic cancer: 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. ^fFondaparinux has not been studied in the outpatient prophylaxis setting. It should only be considered if the patient has contraindications for other LMWH and DOAC use is considered an inferior option.

DOAC Treatments for CAT

References

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