Patients with cancer-associated thrombosis (CAT) are at high risk of recurrent venous thromboembolism (VTE) and major bleeding complications.
1. Introduction
The management of venous thromboembolism (VTE) is a frequent and important clinical issue in patients with cancer. The 6-month VTE risk for patients with cancer is 12-fold higher compared to the general population, and as much as 23-fold higher in patients receiving chemotherapy or targeted therapy
[1]. Over the past two decades, the 12-month cumulative incidence for VTE has increased three-fold in cancer patients
[1]. Furthermore, thromboembolism has been reported to be the second leading cause of death in patients with cancer, highlighting the importance of urgently initiating therapeutic dosing of anticoagulation
[2][3]. However, the management of anticoagulant therapy for cancer-associated thrombosis (CAT) is complex due to an increased risk of both recurrent VTE and major bleeding in patients with cancer as compared to those without cancer
[4][5]. Selection and dosing of anticoagulant therapy for CAT needs to be individualized based on the patient’s risk for both recurrent VTE and bleeding. This can be influenced by patient characteristics, type and stage of cancer, and anticancer treatment
[4][5].
2. Discussion
2.1. Efficacy and Safety of Anticoagulants
Until the publication of randomized controlled trials (RCTs) comparing DOACs with LMWH for the acute treatment of CAT (
Table 1), clinical practice guidelines recommended the use of LMWH over DOACs or VKA for the acute and secondary prevention of VTE in patients with cancer
[6][7]. Recent guidelines, on the other hand, have suggested that either a DOAC or LMWH can be used for the acute treatment of CAT
[8][9][10][11][12], with recommendations that treatment be individualized based on patient characteristics.
Table 1. Randomized controlled trials for the acute treatment of cancer-associated thrombosis.
Reference (Study Name) |
Patients (n) |
Intervention |
Duration (Months) |
Major Bleeding (%) b |
Recurrent VTE (%) b |
Death (%) b |
LMWH compared with VKA |
Meyer et al. 2002 (CANTHANOX) [13] |
67 |
Enoxaparin 1.5 mg/kg daily |
3 |
7 |
3 |
22.7 |
71 |
VKA |
16 |
4.2 |
11.3 |
Lee et al., 2003 (CLOT) [14] |
336 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
6 |
4 |
9 |
39 |
336 |
VKA |
6 |
17 |
41 |
Deitcher et al. 2006 (ONCENOX) a [15] |
29 |
Enoxaparin 1 mg/kg daily |
3 |
6.5 |
6.9 |
6.5 |
32 |
Enoxaparin 1.5 mg/kg daily |
11.1 |
6.3 |
19.4 |
30 |
VKA |
2.9 |
10 |
8.8 |
Hull et al. 2006 (LITE) [16] |
100 |
Tinzaparin 175 IU/kg daily |
3 |
7 |
6 |
19 |
100 |
VKA |
7 |
10 |
20 |
Lee et al. 2015 (CATCH) [17] |
449 |
Tinzaparin 175 IU/kg daily |
6 |
2.7 |
7.2 |
33 |
451 |
VKA |
2.4 |
10.5 |
31 |
DOAC compared with LMWH |
Raskob et al. 2018 |
p = 0.004) and compared to enoxaparin in patients with luminal GI cancer (15.6 vs. 3.2,
p = 0.04)
[35]. Hence, all DOACs should be use cautiously in patients with GI cancers, especially in those with unresected luminal tumors.
Other patient characteristics are also important for clinicians to consider. Subgroup analyses of major bleeding in the Hokusai-VTE Cancer safety population suggest that, in addition to GI cancer, other features associated with a higher risk of major bleeding include urothelial cancer, renal impairment, thrombocytopenia, intracranial malignancy, regionally advanced or metastatic cancer, recent surgery, and use of antiplatelet agents or bevacizumab
[18]. Analysis of clinically relevant bleeding events in the CATCH trial confirmed that intracranial malignancy increases the risk of bleeding regardless of the type of anticoagulation
[36]. Age > 75 years was also significantly associated with an increased risk of clinically relevant bleeding in this analysis
[36].
The Hokusai-VTE Cancer, SELECT-D, and CARAVAGGIO trials have reported greater proportions of DOAC-treated patients who experienced clinically relevant non-major bleeding (CRNMB) events with HRs of 1.38 (95% CI 0.98 to 1.94), 3.76 (95% CI 1.63 to 8.69), and 1.42 (95% CI 0.88 to 2.30) for edoxaban, rivaroxaban, and apixaban, respectively
[18][19][21]. In the Hokusai-VTE Cancer trial, CRNMB events were numerically more common for GI, epistaxis, hematuria, or abnormal uterine bleeding in patients receiving edoxaban compared to those receiving dalteparin
[33]. In SELECT-D, the significantly higher rates of CRNMB in patients receiving rivaroxaban were due to GI and GU bleeding, which accounted for 9 and 11 of the 25 CRNMB events, respectively
[19]. In CARAVAGGIO, the numerical increase in CRNMB was largely due to bleeding in the GU and upper airway tracts, which accounted for 20 and 14 cases, respectively, of the 59 CRNMB events in patients receiving apixaban
[34]. Additionally, patients with GI cancer appeared to be at higher risk of bleeding events with DOAC, with 13.2% (19/144) of patients with GI cancer who were treated with apixaban experiencing CRNMB as compared to 4.9% (7/144) in the dalteparin arm
[34]. Overall, GI or GU CRNMB may be more common in patients receiving a DOAC than in those treated with LMWH.
2.4.1. Features Consistent with a High Risk of GI Bleeding
Given that bleeding rates appear to be higher with DOACs in patients with GI tumors or those on treatments such as bevacizumab that are associated with tumor necrosis and bleeding
[18][19][33][34], the committee suggests considering the use of LMWH for patients with these or other features that are associated with a high risk of GI bleeding, such as angiodysplasia, GI lesion, previous variceal bleed, or treatment-associated mucosal toxicity. The risk of GI perforation and/or hemorrhage associated with a patient’s anticancer therapies should be taken into consideration regardless of which anticoagulant is selected.
2.4.2. Thrombocytopenia
Thrombocytopenia increases the risk of bleeding complications in patients with CAT
[37]. Unfortunately, there is limited evidence to guide management in patients with platelet counts <50,000 platelets/mL. The CLOT trial excluded patients with baseline platelet counts <75,000 platelets/mL, while the Hokusai-VTE Cancer, CARAVAGGIO, and SELECT-D trials excluded patients with baseline platelet counts of less than 50,000, 75,000, and 100,000 platelets/mL, respectively
[14][18][19][21]. Guidance from the SSC of the ISTH suggests that therapeutic dose of anticoagulation can be used for patients with platelet count of ≥50,000 platelets/mL
[38]. In patients with platelet counts of less than 50,000 platelets/mL, 50% or prophylactic dose LMWH may be used or full-dose anticoagulation with platelet transfusion support may be considered
[38]. The Canadian consensus committee suggests that LMWH is preferred in these patients but recommends seeking an expert opinion from a specialized physician when initiating anticoagulation in the setting of severe thrombocytopenia (i.e., platelet counts <50,000/mL). In cases of transient thrombocytopenia due to anticancer therapies, clinical judgment should be used to determine whether the anticoagulant needs to be dose-reduced or temporarily held until platelet levels recover to ≥50,000 platelets/mL.
2.4.3. Intracranial Lesions
As there were few patients with intracranial tumors (primary brain tumor or brain metastasis) included in the DOAC trials (none in CARAVAGGIO, 7% of patients (74/1046) in Hokusai VTE Cancer, and only 1% of patients in SELECT-D), there are limited data regarding the safety of this anticoagulant class in these patients
[18][19][21]. Some reassurance may be provided by a retrospective cohort study of the cumulative incidence of intracranial hemorrhage (ICH) with DOAC vs. LMWH in patients with brain tumors and VTE
[39]. In this study, no ICH was noted among 20 patients with primary brain tumors treated with DOACs, while the cumulative incidence among the 47 patients treated with LMWH was 37%. Among 105 patients with brain metastases, the cumulative incidence of ICH was 11% among those treated with DOAC and 18% in those treated with LMWH
[39]. Similarly, an international two-center study suggested comparable safety of LMWH and DOACs in patients with brain metastases. The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (HR: 0.45; 95% CI 0.09 to 2.21)
[40]. When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH-treated patients (HR: 0.98; 95% CI 0.28 to 3.40)
[40]. Finally, a single-center retrospective chart review of 125 patients with primary and metastatic brain tumors on anticoagulation reported rates of major bleeding of 26% and 9.6% in patients receiving LMWH or DOAC, respectively
[41]. Patients receiving DOAC also had a lower rate of ICH compared to those receiving LMWH (5.8% vs. 15%)
[41]. Nevertheless, given the small numbers and the limitations of retrospective studies, as well the shorter half-life of LMWH, the consensus committee suggests considering the initial use of LMWH for patients with CAT and high-risk intracranial lesions (e.g., glioma).
2.4.4. Hepatic and Renal Impairment
Patients with functional hepatic impairment may have reduced ability to metabolize DOACs, all of which are at least partially metabolized by cytochrome P450 (CYP) enzymes
[42][43][44]. Patients with significant liver disease are thus considered to be at higher risk of bleeding when treated with DOACs and were excluded from clinical trials. For these reasons, none of the DOACs are recommended for use in patients meeting criteria for Child-Pugh class C
[42][43][44]. Rivaroxaban is contraindicated in patients with hepatic disease (including Child-Pugh class B and C) associated with coagulopathy and having clinically relevant bleeding risk
[42]. Apixaban should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B)
[43]. With edoxaban, patients with Child-Pugh class A or B exhibited comparable pharmacokinetics and pharmacodynamics to healthy controls
[44].
The previous iteration of the Canadian expert consensus treatment algorithm suggested that LMWH might be preferable to DOAC in patients with CAT and a creatinine clearance of 30–50 mL/min, especially if additional risk factors for bleeding were present
[8]. This recommendation was based on the limited evidence available at the time suggesting a potentially elevated risk of bleeding with edoxaban in these patients
[18][8]. However, this recommendation was not supported by the CARAVAGGIO trial, which found no significant between-treatment differences in rates of major bleeding in patients with creatinine clearance of 30–80 mL/min treated with apixaban or LMWH
[21]. Thus, the consensus committee currently recommends that clinicians follow product monograph recommendations for contraindications and dose adjustment of anticoagulants in patients with impaired renal function (
Table 2).
Table 2. Product monograph dosing recommendations according to creatinine clearance.
Anticoagulant |
Creatinine Clearance (mL/min) |
<15 or Dialysis |
15–29 |
30–50 |
>50 |
LMWH |
Dalteparin [45] |
Dose reduction should be considered a |
Dose reduction should be considered a |
200 IU/kg once daily for 1 month, and then 150 IU/kg |
200 IU/kg once daily for 1 month, and then 150 IU/kg |
Enoxaparin [46] |
100 IU/kg once daily |
100 IU/kg once daily |
100 IU/kg twice daily |
100 IU/kg twice daily |
Tinzaparin [47] |
175 IU/kg once daily a |
175 IU/kg once daily a |
175 IU/kg once daily |
175 IU/kg once daily |
DOAC |
Apixaban [43] |
Not recommended |
10 mg twice daily for 7 days, and then 5 mg twice daily b |
10 mg twice daily for 7 days, and then 5 mg twice daily b |
10 mg twice daily for 7 days, and then 5 mg twice daily b |
Edoxaban [44] |
Not recommended |
Not recommended |
30 mg once daily (following initial 5–10 days of LMWH) |
60 mg once daily (following initial 5–10 days of LMWH) |
Rivaroxaban [42] |
Not recommended |
15 mg twice daily for 3 weeks, and then 20 mg once daily b |
15 mg twice daily for 3 weeks, and then 20 mg once daily b |
15 mg twice daily for 3 weeks, and then 20 mg once daily b |
|
(Hokusai-VTE Cancer) |
[ |
18 |
] |
522 |
LMWH for ≥5 days, and then edoxaban 60 mg daily |
12 |
6.9 |
7.9 |
39.5 |
524 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
4.0 |
11.3 |
36.6 |
Young et al. 2018 (SELECT-D) [19] |
203 |
Rivaroxaban 15 mg twice daily for 3 weeks, and then 20 mg daily |
6 |
6 |
4 |
25 |
203 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
4 |
11 |
30 |
McBane et al. 2020 (ADAM-VTE) [20] |
145 |
Apixaban 10 mg twice daily for 7 days, and then 5 mg twice daily |
6 |
0 |
0.7 |
16 |
142 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
1.4 |
6.3 |
11 |
Agnelli et al. 2020 (CARAVAGGIO) [21] |
576 |
Apixaban 10 mg twice daily for 7 days, and then 5 mg twice daily |
6 |
3.8 |
5.6 |
23.4 |
579 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
4.0 |
7.9 |
26.4 |
Planquette et al. 2021 (CASTA-DIVA) [22] |
74 |
Rivaroxaban 15 mg twice daily for 3 weeks, and then 20 mg daily |
3 |
1.4 |
6.0 |
25.7 |
84 |
Dalteparin 200 IU/kg daily for 1 month, and then 150 IU/kg |
|
3.7 |
9.5 |
23.8 |