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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 46-53

Direct oral anticoagulants in cancer-associated venous thromboembolism


Department of General Surgery and Radiology, Pirogov Russian National Research Medical University, Moscow, Russian Federation , Russian Federation

Date of Submission06-May-2020
Date of Decision08-Jun-2020
Date of Acceptance11-Jun-2020
Date of Web Publication09-Jul-2020

Correspondence Address:
Dr. Irina Kanzafarova
10 Pistsovaya Str., Clinical Hospital No 24, Department of General Surgery and Radiology, Moscow, 127015
Russian Federation
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_11_20

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  Abstract 


This is a narrative review of the relevant literature on the epidemiology, pathogenesis, and treatment of venous thromboembolism (VTE) in cancer patients. In accordance with actual guidelines, the duration of anticoagulant therapy for cancer-associated venous thrombosis should be at least 6 months. The use of Vitamin K antagonists (VKA) is associated with an increased risk of VTE recurrence and bleeding, so low-molecular-weight heparin (LMWH), in particular dalteparin, has been the “gold standard” until recently. Compared to VKA, prolonged use of LMWH can reduce the incidence of VTE recurrence without affecting the risk of bleeding or death. The main disadvantage of LMWH is low compliance, leading to premature discontinuation of treatment or switching to alternative anticoagulants. Direct oral anticoagulants (DOACs) have changed the situation. Compared to VKA, they demonstrated increased efficacy with similar or improved safety in patients with cancer-related VTE. Recently, the results of specialized studies comparing the use of DOACs to the use of dalteparin in cancer patients have been published: SELECT-D (rivaroxaban), HOKUSAI-VTE Cancer (edoxaban), ADAM VTE (apixaban), and CARAVAGGIO (apixaban). Rivaroxaban showed higher efficacy than dalteparin with a similar risk of major bleeding, but with an increased risk of clinically relevant nonmajor (CRNM) bleeding. Edoxaban had the same efficacy as dalteparin, though it showed an increased risk of major but not CRNM bleeding. Apixaban showed similar efficacy and safety as dalteparin in the CARAVAGGIO study, but did not provide higher safety in the ADAM VTE study. It was noted that gastrointestinal and urogenital bleeding dominated the structure of hemorrhagic complications of DOACs. The results of published trials are reflected in the current guidelines of the specialized societies. DOACs are recommended for VTE treatment in cancer patients.

Keywords: Direct oral anticoagulants, malignancy, pulmonary embolism, venous thromboembolism, venous thrombosis


How to cite this article:
Lobastov K, Schastlivtsev I, Kanzafarova I. Direct oral anticoagulants in cancer-associated venous thromboembolism. Vasc Invest Ther 2020;3:46-53

How to cite this URL:
Lobastov K, Schastlivtsev I, Kanzafarova I. Direct oral anticoagulants in cancer-associated venous thromboembolism. Vasc Invest Ther [serial online] 2020 [cited 2020 Aug 11];3:46-53. Available from: http://www.vitonline.org/text.asp?2020/3/2/46/289239



One can find a strong relationship between active cancer and venous thromboembolism (VTE). A malignant tumor is a moderate risk factor for VTE, increasing the risk by 3- to 7-fold.[1],[2] The incidence of VTE reaches 10%–20% in patients with active cancer.[3],[4],[5],[6],[7] A medical history of venous thrombosis defines the unfavorable outcome of cancer. In cancer-associated thrombosis (CAT), clinicians can see a higher frequency of readmissions and mortality rates in compared to isolated malignancy and thrombosis.[8] It is significant when thrombosis cooccurs with cancer, but the history for VTE within 1 year is also significant.[9] VTE may be a sign of progressive cancer disease with distant metastases and poor outcomes.[9]

Deep venous thrombosis (DVT) and pulmonary embolism (PE) can develop in a patient with confirmed cancer or can precede the diagnosis of a malignancy. Usually, it happens within 1 year around cancer verification.[3],[10] However, there is evidence of an increased risk of VTE at 10–15 years after a cancer diagnosis.[3] On the other hand, the risk of verification of specific malignancies (colon cancer, pancreatic cancer, and myeloma) may be increased at six or more years after index VTE.[10] One could assume that there is a common genetic background between VTE and cancer disease.

The specific thrombogenic mechanisms of malignancy include the following:

  • Expression of tissue factor and proteases directly on the cancer cell membrane that promotes contact activation of coagulation factors and initiation of the coagulation process
  • Neutrophil recruitment and activation with subsequent formation of neutrophil extracellular traps that contain nuclear DNA and that can activate platelets
  • Formation of microparticles that express tissue factor on their membrane (TF-microparticles).[11]


The last-mentioned mechanism deserves detailed consideration due to its importance in CAT pathogenesis, as was reported in recent years.[12]

Microparticles represent a phospholipid vesicle with a diameter of 50–1000 nm that are secreted by cells due to membrane outpouching and subsequent budding. A parental cell's membrane covers the formed vesicle with a specific set of markers. Furthermore, it contains parental cytoplasm with the possible presence of RNA fragments and biologically active substances. Procoagulant microparticles derived from platelets, leukocytes, endotheliocytes, and tumor cells express on their surface tissue factor, usually in complex with VIIa factor, phosphatidylserine, and cell adhesion molecules (receptors for P- and E-selectin). In addition, tumor-derived TF-microparticles represent specific markers of parental cells that could be identified in laboratory tests. The clinical significance of the tumor-derived TF-microparticles was assessed in several studies combined in the meta-analysis.[12] Five retrospective studies demonstrated a significantly increased level of TF-microparticles in patients with CAT compared to those with cancer but without VTE. Five prospective studies showed a significant predictive value of TF-microparticles on the development of the CAT during a 2-year follow-up. However, two other prospective studies did not confirm these findings. Possibly, this difference is related to the type of tumor. An increased level of TF-microparticles is more common among gastric, hepatic, biliary, and pancreatic malignancies, but rarely occurs in brain tumors in the absence of surgery (intact blood-brain barrier), and they are not expressed by myeloma cells.[12],[13] In the case of pancreatic cancer, the level of TF-microparticles correlates not only with the risk of VTE but also with overall mortality.[14]

The complex of described molecular and cellular mechanisms underlies the specific thrombophilic status in cancer disease that could be detected by global tests for hemostasis.[15] In particular, the thrombodynamics test reveals hypercoagulation in 65% of patients with colorectal cancer, which accurately correlates with the incidence of postoperative VTE.[16]

Malignancy is a moderate risk factor for VTE that fulfills its thrombogenic potential with other provocative factors.[6] Barsam et al. divided these triggers into three groups: related to the tumor specifics, the individual risk factors, and the invasive and noninvasive treatment [Table 1]. All of them are represented within the different models for VTE risk assessment. For cancer surgery, the Caprini score (2005) is the most validated risk assessment model.[17] For individuals receiving chemotherapy as outpatients, several models were proposed: the original Khorana score (2008),[18] the modified Khorana score (2010),[19] and the nomogram (2018).[20] For acutely ill medical patients, the Padua score (2010) is recommended.[21]
Table 1: Risk factors for cancer-related venous thromboembolism[6]

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The treatment of cancer-associated VTE is challenging due to the combination of high risk for fatal PE and fatal bleeding in one patient.[22] In the absence of malignancy, the period of anticoagulation therapy is usually divided into three phases: the initial treatment (up to seven days), the long-term treatment (up to three months), and the prolonged treatment (beyond three months). The minimal duration of therapy is 3 months, and indications for extended treatment are based on the clinical characteristics of the index episode.[23],[24] For cancer-associated VTE, the time frame is changing: the initial treatment lasts five to 10 days, the long-term treatment extends to up to 6 months, and the prolonged treatment is for longer than 6 months. The minimal duration of anticoagulation therapy is 6 months, and the indication for prolonged treatment is based on the cancer activity (presence of distant metastases and/or need for specific therapy).[25] Besides the duration of anticoagulation, the list of recommended medications and their dosing is also specified.

The long-term use of Vitamin K antagonists (VKA) is not an optimal strategy for CAT. In comparison to patients without malignancies, those with cancer have a 3.2-fold increased risk of VTE recurrence with a 2.2-fold increased risk of major bleeding when they are treated with VKA for 12 months.[26] Until recently, low molecular weight heparins (LMWH) were considered a “gold standard” for CAT treatment. This recommendation was initially based on the results of the CLOT trial.[27] In this study, dalteparin (200 IU/kg for the 1st month reduced to 150 IU/kg for the subsequent 5 months), in comparison to VKA, decreased the risk of VTE recurrence by 52% for 6 months, without affecting bleeding risk and overall mortality. The subsequent meta-analyses confirmed the advantages of different LMWH: Compared to VKA, they reduced the risk of VTE recurrence by 42%–44% without any influence on the bleeding rate and overall mortality.[28],[29] The main drawback of LMWH is the need for injections, which limits compliance with the proposed treatment. The analysis of medical and pharmacy claims from the Humana Database found that the average duration of treatment with LMWH was 3.3 months (vs. 7.9 months with oral anticoagulants), and the recommended 6-month therapy was completed by only 37% of patients (vs. 61% with oral anticoagulants).[30]

The introduction of direct oral anticoagulants (DOACs) revealed new opportunities for VTE treatment in cancer patients. The efficacy and safety of DOACs were initially assessed in Phase III registrational trials that enrolled patients with active cancer, or those with malignancy detected during follow-up. For rivaroxaban, it was EINSTEIN DVT and PE (665 cancer patients),[31] for apixaban – AMPLIFY (169 cancer patients),[32] for edoxaban – HOKUSAI-VTE (208 cancer patients),[33] and for dabigatran – RE-COVER I and II (355 cancer patients).[34] The meta-analysis of these trials found the superiority of DOACs over VKA: The risk of VTE recurrence was reduced by 35% without affecting the risk of bleeding and overall mortality.[29] Moreover, Xa-factor inhibitors showed additional advantages in terms of efficacy (recurrent VTE risk reduction by 36%) and safety (major bleeding risk reduction by 55%). The EINSTEIN DVT and PE trials included the largest number of patients with cancer-associated VTE that is comparable with the CLOT patient sample (655 vs. 676 participants). The trials demonstrated a significant reduction in the risk of major bleeding by 55% and a combined endpoint of VTE recurrence and major bleeding by 44% in cancer patients.[31] After that, rivaroxaban became widespread for the treatment of CAT. A systematic review conducted in 2019 revealed 13 trials with 5480 cancer patients, among whom about 90% used rivaroxaban.[35]

The next step in assessing DOAC's efficacy and safety in cancer patients was the conducting of specific trials. For rivaroxaban, it was SELECT-D,[36],[37] for apixaban – ADAM VTE[38] and CARAVAGGIO,[39] and for edoxaban – HOKUSAI-VTE Cancer.[40] Their general characteristics are summarized in [Table 2], [Table 3], [Table 4]. All trials were randomized and open-label (it has been acknowledged as unethical to use a parenteral placebo in cancer patients) and evaluated the efficacy and safety of full doses of DOACs in comparison to “gold standard” dalteparin (full dose for the 1st months with a further reduction to an intermediate dose).
Table 2: General characteristics of specialized studies on direct oral anticoagulants in cancer-related venous thromboembolism

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Table 3: Characteristics of malignancies included in specialized studies on DOACs in cancer-related VTEs

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Table 4: The results of specialized studies on direct oral anticoagulants in cancer-related venous thromboembolisms

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The SELECT-D was a pilot study aimed at recruiting 500 patients with CAT to assess the efficacy and safety of a standard 6-month course of anticoagulation. After that, at least 300 participants planned to undergo secondary randomization for prolonged treatment. Patients with active cancer and symptomatic proximal lower extremity DVT, symptomatic, or incidental (detected with imaging not aimed at VTE diagnosis) PE were randomly allocated to receive either rivaroxaban or dalteparin. In 6 months, it was proposed that all participants who were initially diagnosed with PE or in whom the residual venous obstruction (the residual thrombus occupies over 40% of the vessel cross-section diameter) was identified via duplex ultrasound should undergo secondary randomization. Those who agreed to continue the trial were allocated to receive rivaroxaban (20 mg) or placebo for the additional 6 months. Subjects without PE at baseline and without signs of residual venous obstruction at 6 months were followed without additional treatment. The rationale behind such a design was based on the results of the previous Cancer-DACUS trial.[41] It showed that patients with CAT and persistent residual venous obstruction after 6 months of therapy with LMWHs are characterized by a 6-fold (95% confidence interval [CI], 1.7–21.2) increased risk of VTE recurrence during the next 12 months, and that extended use of LMWHs did not affect this risk.

The first part of the SELECT-D trial enrolled 406 patients, who were equally allocated into two groups of 203 participants.[36] At 6 months, rivaroxaban showed superiority over dalteparin in terms of VTE recurrence (hazard ratio [HR], 0.43; 95% CI, 0.19–0.99). It did not affect the risk of major bleeding (HR, 1.83; 95% CI, 0.68–4.96), but did increase the rate of clinically relevant nonmajor (CRNM) bleeding (HR, 3.76; 95% CI, 1.63–8.69) mainly from the gastrointestinal (GI) tract and genitourinary tract. Notably, GI cancers accounted for 35% of all tumors, while GI bleedings dominated in the structure of major hemorrhagic complications accounting for 72%. No significant difference in overall mortality was observed, but numerically, mortality was lower in the rivaroxaban group.

One hundred and twenty-seven patients continued to participate in the extended phase of the SELECT-D trial. Ninety-two subjects had DVT that resulted in residual venous obstruction or PE as an index event and were secondarily randomized into two groups of 46 participants. Thirty-five patients did not have either residual obstruction or PE and were followed without treatment. In 6 months, VTE recurrence was registered in two (4%) patients in the rivaroxaban group and six (14%) patients in the placebo group, though not in any participant in the nontreatment group. Despite the observed trend, the study was underpowered to detect a significant difference in the risk of recurrent VTE (HR, 0.32; 95% CI, 0.06–1.58). Bleeding was observed only in the rivaroxaban group: two cases of major and two cases of CRNM bleedings without lethal outcomes. Therefore, rivaroxaban was superior to dalteparin and did not increase the risk of major bleeding during the long-term therapy of cancer-associated VTE.

The HOKUSAI-VTE Cancer was a noninferiority trial comparing edoxaban and dalteparin by a composite endpoint of VTE recurrence with major bleeding.[40] It enrolled patients with active or historical (within two years) cancer and signs of symptomatic or incidental proximal DVT and PE. Edoxaban was used in the full therapeutic dose, while dalteparin required a standard dose reduction after the 1st months. The overall treatment duration varied from six to 12 months. Overall, 1050 patients with different tumors were enrolled. The primary composite endpoint occurred in 12.8% of patients who received edoxaban, and in 13.5% who received dalteparin (HR, 0.97; 95% CI, 0.7–1.36; P = 0.006 for noninferiority; P = 0.87 for superiority). The incidence of VTE recurrence (taking into account not only symptomatic, but also incidental proximal DVT and PE, and any fatal outcome with nonexcluded PE) favored edoxaban, though the difference did not reach statistical significance (HR, 0.71; 95% CI, 0.48–1.06; P = 0.09 for superiority). The risk of major bleeding was significantly higher for edoxaban (HR, 1.77; 95% CI, 1.03–3.04; P = 0.04 for superiority). The risk of CRNM bleeding did not differ (HR, 1.38; 95% CI, 0.98–1.94). The bleedings from GI (which accounted for 60% of all major bleedings) and the genitourinary system dominated in the structure of major hemorrhagic complications. In the majority of cases, major bleeding was associated with GI cancer. Nevertheless, the incidence of severe major bleeding (3–4 category by study classification) did not differ between groups in the general population (1.9% in the edoxaban group and 2.1% in the dalteparin group) and in patients with GI tumors (3.0% vs. 2.1%, respectively).[42] No difference in overall mortality was detected. The long-term and prolonged anticoagulation therapy for CAT with edoxaban was noninferior to dalteparin on the composition of efficacy and safety. A trend in the reduction of VTE recurrence along with the significantly increased risk of major (but not CRNM) bleeding was observed.

The ADAM VTE was a superiority trial aimed at demonstrating the improved safety of apixaban compared to dalteparin.[38] The inclusion criteria were not limited by instrumentally verified lower limb DVT or PE but suggested upper extremity DVT, splanchnic, and cerebral vein thrombosis. Patients were randomly allocated to receive apixaban or dalteparin at the standard doses for 6 months. The study appeared to be underpowered to demonstrate a significant difference in the primary endpoint of major bleeding. It occurred in none of the 145 patients who received apixaban and in two of the 142 (2.1%) patients who were treated with dalteparin. There was no difference in the rate of major and CRNM bleeding: 6.2% on apixaban and 6.3% on dalteparin. The secondary efficacy endpoint of any VTE or arterial thrombosis was observed in one (0.7%) patient on apixaban and nine (6.3%) patients on dalteparin (HR, 0.099%, 95% CI, 0.013–0.78; P = 0.0281). The overall mortality did not differ between the groups; however, numerically, the mortality was higher in subjects on apixaban (16% vs. 11%). Thus, the ADAM VTE trial failed to demonstrate the advantages of apixaban over dalteparin in terms of safety.

The CARAVAGGIO was designed as a noninferiority trial aimed at confirming the same efficacy of apixaban as compared to dalteparin within 6 months of treatment for CAT.[39] The study enrolled patients with active or historical (within two years) cancer, and symptomatic or incidental proximal DVT or PE. Among the aforementioned studies, it is the only that excluded primary or metastatic brain tumor. In total, 1170 patients were randomized. No significant difference was observed for the primary efficacy endpoint that consisted of symptomatic or incidental proximal DVT or PE, as well as symptomatic upper extremity DVT (HR, 0.63; 95% CI, 0.37–1.07; P < 0.001 for noninferiority; P = 0.09 for superiority). Therefore, in terms of efficacy, apixaban appeared to be noninferior to dalteparin but failed to prove superiority despite the obvious trend. No significant difference in major (HR, 0.82; 95% CI, 0.40–1.69; P = 0.60) and CRNM bleedings (HR, 1.42; 95% CI, 0.88–2.30) was detected. The major GI bleeding was added as an additional safety endpoint after the publication of the SELECT-D and HOKUSIA-VTE cancer trials' results. No difference in this endpoint was observed (HR, 1.05; 95% CI, 0.44–2.50), but GI bleedings accounted about half of major hemorrhagic complications. Overall mortality did not differ between the groups (23.4% vs. 26.4%). Therefore, apixaban was confirmed as being noninferior to dalteparin in terms of efficacy and safety in cancer patients with VTE. Because the number of included patients with GI malignancies was limited, and because the study power was not designed to demonstrate the difference in this endpoint, the statement about apixaban as the safest DOAC in terms of GI tumors and GI bleedings is premature.

The overall mortality in cancer patients receiving DOACs was studied in one recent trial of real clinical practice. It compared VTE recurrence, bleeding, and mortality rates in patients with CAT on rivaroxaban, apixaban, and enoxaparin.[43] There was no significant difference in VTE recurrence (3.82, 7.74, and 5.56 cases 100 patient-years) or major bleeding (6.74, 7.73, and 6.99 cases per 100 patient-years for rivaroxaban, apixaban, and enoxaparin, respectively). However, the number of fatal outcomes was significantly lower in the patients on rivaroxaban: 39.3 cases in 100 patient-years compared to 55.7 cases on apixaban and 53.8 cases on enoxaparin. One can assume that there are possible antiproliferative properties of individual anticoagulants that need further investigation.

The new studies on DOACs in cancer patients have demonstrated good efficacy and safety profiles in comparison to dalteparin, which, until recently, was the “gold standard” of anticoagulation therapy. Rivaroxaban appeared to be more effective with a comparable risk of major bleedings and increased risk of CRNM bleeding. Edoxaban has shown equivalent efficacy with an increased risk of major but not CRNM bleeding. Apixaban proved to not be less effective and safe in regards to major and CRNM bleeding. Globally, all DOACs tend to reduce the risk of VTE recurrence and increase the risk of bleeding. Most likely, this trend is related to the fixed full-dose of DOAC used throughout the entire period of treatment. At the same time, the dose of active comparator was decreased by 25% after 30 days of therapy. This suggestion is supported by survival curves that diverge significantly after 1 month of observation. Thus, the risk/benefit profile of DOACs in cancer patients may be slightly shifted toward increased efficacy at the cost of elevated bleeding risk. One can assume that the dose reduction of DOACs can improve this risk/benefit balance. However, this should be confirmed in further randomized trials.

The results of cited studies have been reflected in the current guidelines on the treatment of VTE in cancer patients. They are summarized in [Table 5]. To date, the majority of international societies recommend rivaroxaban and edoxaban for use in cancer patients. Apixaban inclusion in the guidelines is expected in the near future.
Table 5: Current guidelines of specialized societies on the use of direct oral anticoagulants in cancer-related venous thromboembolism

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[45]

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Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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