Cancer-associated venous thromboembolism: Treatment and prevention with rivaroxaban.

Essentials

Cancer‐associated thrombosis (CAT) is a frequent complication of cancer management.

Direct oral anticoagulants (DOACs) have been demonstrated to be a noninferior treatment option to low‐molecular‐weight heparin.

Recent studies have highlighted a potential role for DOACs in CAT prevention.

INTRODUCTION

Cancer‐associated thrombosis (CAT) is a frequently encountered, life‐threatening event that complicates cancer management and decreases survival. 1 , 2 Cancer and anticancer treatments are well‐established risk factors for venous thromboembolism (VTE), and cancer increases the risk of VTE 4‐ to 7‐fold versus patients without cancer. 3 CAT makes a significant contribution to the burden of VTE, accounting for approximately 20% of all cases. 4 Anticoagulants are the cornerstone for the primary prevention and treatment of VTE but may be underused for CAT because of complications in management specific to patients with cancer. 5

Direct oral anticoagulants (DOACs) are used for the prevention and treatment of thromboembolic events across several indications, including VTE. The direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban (and to a lesser extent the direct thrombin inhibitor dabigatran) have been investigated in studies of the prevention 6 , 7 , 8 and treatment 9 , 10 , 11 , 12 , 13 , 14 , 15 of VTE in patients with cancer; results from many of these studies are now published. 6 , 7 , 9 , 10 , 11 This review details the rationale, study designs, and results (where applicable) of completed and ongoing investigations of DOACs in CAT, with a focus on rivaroxaban and the studies in the CALLISTO (Cancer Associated thrombosis—expLoring soLutions for patients through Treatment and Prevention with RivarOxaban) program (Tables 1 and 2 ). The aim is to provide an update to a previously published review of the CALLISTO program 1 .

RATIONALE FOR STUDYING THE USE OF DOACs FOR CAT

To broaden the anticoagulant options available

The availability of DOACs for the prevention and treatment of CAT broadens the anticoagulation therapy options for patients with cancer, to address issues associated with traditional options. Parenteral anticoagulants such as unfractionated heparin, and subcutaneously injectable low‐molecular‐weight heparin (LMWH) and fondaparinux are traditional options for the prevention of VTE in ambulatory patients with cancer at a high‐risk of VTE (Table 3 ) 16 , 17 , 18 , 19 , 20 , 21 and in the treatment of CAT (Table 4 ). 16 , 17 , 18 , 19 , 20 , 22 Parenteral anticoagulants may not be convenient for long‐term therapy, and some patients may prefer an oral drug. Until recently, vitamin K antagonists (VKAs) were the only oral alternative to parenteral drugs endorsed by international guidelines for CAT treatment, but were known to be less efficacious than LMWH in this setting 23 , 24 , 25 , 26 ; therefore, LMWHs were preferred in guidelines. There is also no evidence to support the use of parenteral anticoagulants in patients with atrial fibrillation (AF), complicating management of patients with CAT and AF. These challenges and the rationale for DOAC use in cancer‐associated VTE will be explored in more detail.

To improve persistence with anticoagulation therapy

CAT management benefits from the availability of parenteral anticoagulants, particularly for patients experiencing nausea and vomiting or impaired gastrointestinal absorption. Long‐standing experience with LMWH use, and the flexible LMWH dose adjustments, allows for easier or more flexible management of thrombocytopenia and invasive interventions than with other anticoagulants, for example, VKAs. 19 , 27 , 28 Challenges with parenteral administration (eg, inconvenience and discomfort of daily injections), alongside the high cost of LMWHs, 27 , 29 may be burdensome for patients needing long‐term anticoagulation therapy; CAT treatment guidelines support anticoagulation therapy for at least 3 to 6 months for the prevention of recurrent VTE. 16 , 17 , 18 , 19 , 20 , 27

Some challenges of LMWH therapy may underpin poor persistence and the high use of oral anticoagulants, as observed in large US claims database analyses of patients newly diagnosed with cancer and CAT. 30 , 31 , 32 In an analysis of 2941 patients from the US Humana database, many patients switched from index LMWH to warfarin or rivaroxaban therapy (12.0% and 9.9%, respectively) within the 12‐month observation period. 32 In the same study, and in a similar US database analysis of 12 457 patients with CAT, patients who initiated on warfarin or rivaroxaban were significantly more likely to remain on index therapy than patients initiated on an LMWH. 31 , 32 One limitation of such studies is that details of anticoagulant management strategies, including switching anticoagulants for circumstances such as surgery, are easily overlooked. In contrast, persistence with therapy observed in the CLOT (Randomized Comparison of Low‐Molecular‐Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer) and CATCH (Comparison of Acute Treatments in Cancer Hemostasis) trials was higher with LMWH than with VKA therapy. 23 , 26 The DOAC CAT treatment studies were an opportunity to further explore whether an oral anticoagulant could improve treatment persistence.

To provide an oral alternative to VKAs

Difficulties with use of VKAs in CAT include high rates of VTE recurrence (~7%–30% per patient‐year) 1 , 33 ; meta‐analyses indicate that this risk is about 50% lower with LMWH than with VKAs. 34 , 35 Major bleeding rates with VKAs are also high (~5%‐16% per patient‐year), 1 , 33 but the risk is similar to that with LMWH. 34 , 35

These outcomes may be due to challenges in maintaining VKAs within the target therapeutic range for an adequate time 27 ; the mean time in therapeutic range was 46% and 47% in patients treated with warfarin in the CLOT and CATCH studies, respectively. 23 , 26 DOACs overcome some limitations of VKAs, including having more predictable pharmacokinetic profiles. Similar to LMWHs, DOACs do not require regular laboratory monitoring or dose adjustment to maintain the desired anticoagulation effect. Drug–drug interactions (DDIs) and overlapping toxicities can affect the effectiveness and safety of anticoagulants in patients with cancer. DOACs and LMWHs have a lower potential for DDIs than VKAs. 36 , 37 DDIs are important because patients with cancer routinely receive numerous comedications, 36 , 38 but given the rapidly evolving nature of anticancer pharmacology, there is limited knowledge of DDIs between anticoagulants and anticancer therapies. More clinical experience has been gained with LMWH therapy than with DOACs, which might have exposed DDIs through adverse event reporting. This topic is further discussed later in this review.

To provide an efficacious option for patients with CAT and AF

Patients with cancer have a high incidence of AF and stroke. 39 , 40 , 41 DOACs are the preferred option for stroke prevention in patients with nonvalvular AF, 42 , 43 whereas LMWHs are not routinely recommended in this setting due to a lack of evidence (ie, large‐scale trials of LMWH in AF). 42 Use of the most effective anticoagulation therapy is particularly important in these patients because cancer further increases stroke risk in patients with AF. 44 A large Danish nationwide cohort study demonstrated that the absolute risks of thromboembolic and bleeding complications were similar in patients with AF with and without cancer, irrespective of VKA or DOAC prescription. 45 Guidance from the Scientific and Standardization Committee of the ISTH on anticoagulation of patients with cancer with nonvalvular AF receiving chemotherapy has recently been published. 46

EVIDENCE BASE FOR THE USE OF RIVAROXABAN IN CAT

In some clinical circumstances, DOACs are used in VTE prophylaxis in patients without cancer. 47 , 48 Studies specific to VTE prevention in patients with cancer were warranted, given the benefits observed with LMWH for the prevention of CAT in ambulatory patients receiving systemic anticancer therapy in the SAVE‐ONCO (Evaluation of AVE5026 in the Prevention of VTE in Cancer Patients Undergoing Chemotherapy) and PROTECHT (PROphylaxis of ThromboEmbolism during CHemoTherapy) trials. 49 , 50 Data from the AVERT (Apixaban for the Prevention of Venous Thromboembolism in High‐Risk Ambulatory Cancer Patients: A Randomized Placebo‐Controlled, Double‐Blind Clinical Trial) 7 and CASSINI (Efficacy and Safety of Rivaroxaban Prophylaxis Compared With Placebo in Ambulatory Cancer Patients Initiating Systemic Cancer Therapy and at High Risk for Venous Thromboembolism) 6 trials provide valuable insights into apixaban and rivaroxaban, respectively, for CAT prevention in high‐risk patients in the ambulatory setting (Table 5 ).

AVERT

In the AVERT study of thromboprophylaxis with apixaban 2.5 mg twice daily, patients with cancer at high risk of VTE (based on a Khorana score cutoff of ≥ 2 and initiating systemic chemotherapy) were enrolled. 7 , 51 The primary efficacy outcome in AVERT was objectively documented VTE over a 180‐day follow‐up period and the main safety outcome was major bleeding.

Of 574 randomized patients, 563 were included in a modified intention‐to‐treat analysis. VTE occurred in 12 of 288 patients (4.2%) in the apixaban group and 28 of 275 patients (10.2%) in the placebo group (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.26‐0.65; P < .001). In an on‐treatment analysis, VTE occurred in 3 of 288 patients (1.0%) in the apixaban group and in 20 of 275 patients (7.3%) in the placebo group (HR, 0.14; 95% CI, 0.05‐0.42). In the modified intention‐to‐treat analysis, 10 patients (3.5%) in the apixaban group and 5 patients (1.8%) in the placebo group experienced major bleeding (HR, 2.00; 95% CI, 1.01‐3.95; P = .046). Major bleeding occurred during the treatment period in 6 patients (2.1%) in the apixaban group and 3 patients (1.1%) in the placebo group (HR, 1.89; 95% CI, 0.39‐9.24).

CASSINI

CASSINI was a multicenter trial, with a similar study design to AVERT, which assessed rivaroxaban versus placebo for thromboprophylaxis in ambulatory patients with cancer who initiated systemic therapy and had a Khorana risk score ≥ 2. 6 , 52 A major difference in the design of CASSINI versus AVERT is that CASSINI mandated lower‐extremity ultrasonography at baseline (thus excluding any inapparent deep vein thrombosis [DVT] at baseline) and serial time points during the study, and accepted on‐study screen‐detected VTE as an end point, whereas AVERT focused on symptomatic VTE only. 51 , 52 In CASSINI, advanced pancreatic cancer status was used for stratification, as prior to the study, approximately 25% of enrolled patients were expected to have the disease (the actual proportion was 32.6% of randomized patients). The primary efficacy end point was the incidence of the composite of objectively confirmed symptomatic or asymptomatic VTE or VTE‐related death during the 6‐month treatment period. The primary safety end point was ISTH major bleeding events. 6

Overall, 841 patients were randomized; rivaroxaban did not significantly reduce VTE or VTE‐related death in the primary analysis period, largely due to a high rate of treatment discontinuation and/or early mortality. The primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and 37 of 421 patients (8.8%) in the placebo group.

(HR, 0.66; 95% CI, 0.40‐1.09; P = .10) in the intention‐to‐treat population up‐to‐day‐180 observation period, with the majority of events (24/62; 39%) in the rivaroxaban arm occurring after drug discontinuation. In a prespecified analysis of the intention‐to‐treat population for the on‐treatment period, primary end point events were significantly reduced with rivaroxaban versus placebo. In total, 11 of 420 patients (2.6%) in the rivaroxaban group versus 27 of 421 (6.4%) in the placebo group experienced a primary end point event (HR, 0.40; 95% CI, 0.20‐0.80). Major bleeding occurred in 8 of 405 patients (2.0%) and 4 of 404 patients (1.0%) in the rivaroxaban and placebo groups, respectively (HR, 1.96; 95% CI, 0.59‐6.49; P = .26). 6

Table 5 summarizes the key characteristics and data from AVERT and CASSINI. AVERT and CASSINI were the first phase III randomized trials assessing the efficacy and safety of DOAC thromboprophylaxis in higher‐risk outpatients with cancer, and provide the first data on the use of long‐term oral anticoagulation for the primary prevention of VTE in this setting. 1 , 6 , 7 , 52

Hokusai‐VTE‐Cancer

The Hokusai‐VTE‐Cancer study (A Phase IIIb, Prospective, Randomized, Open‐Label, Blind Evaluator Study Evaluating the Efficacy and Safety of LMWH/Edoxaban Versus Dalteparin in VTE Associated With Cancer) was a large, open‐label, noninferiority trial evaluating edoxaban (60 mg once daily, administered after ≥ 5 days of LMWH) versus dalteparin (200 IU/kg once daily for 1 month [capped at a maximum daily dose of 18 000 IU] followed by 150 IU/kg once daily thereafter) for the treatment of CAT. Of the 1050 patients enrolled, 98% had active cancer, 53% had metastatic cancer, 72% were receiving anticancer therapy, and 24% had an Eastern Cooperative Oncology Group (ECOG) status of 2 9 (whereas an ECOG status of 3 or 4 is a criterion for exclusion across CAT treatment trials). 9 , 10 , 23 , 26

The composite outcome of the first recurrent VTE or major bleeding event at 12 months occurred in 12.8% of patients treated with edoxaban compared with 13.5% of patients treated with dalteparin, demonstrating statistically significant noninferiority (HR, 0.97; 95% CI, 0.7‐1.36; P = .0056). Although the median duration of therapy was significantly longer with edoxaban than with dalteparin (211 days vs 184 days, respectively; P = .01), a sensitivity analysis of events that occurred in the per‐protocol population during treatment or ≤ 3 days of discontinuation confirmed noninferiority of the primary outcome. A total of 15% of patients who had permanently discontinued LMWH therapy did so because of the inconvenience of dosing (compared with 4% of patients on oral edoxaban therapy). Recurrent VTE risk was initially similar between treatment arms, but the Kaplan–Meier curves separated from approximately day 100 in favor of edoxaban. This led to a numerically but not significantly lower risk of recurrent VTE with edoxaban compared with dalteparin treatment (7.9% vs 11.3%; HR, 0.71; 95% CI, 0.48‐1.06; P = .09), driven by a reduction in the rate of recurrent DVT (3.6% vs 6.7%; HR, 0.56; 95% CI, 0.32‐0.97). The rate of recurrent pulmonary embolism was similar between treatment arms (5.2% vs 5.3%; HR, 1.00; 95% CI, 0.59‐1.69). 9 Reassuringly, the risk of recurrent VTE at 6 months with dalteparin therapy (8.8%) 9 was similar to that observed in previous trials of dalteparin for CAT. 23 , 53

The incidence of major bleeding was significantly higher in patients treated with edoxaban compared with dalteparin (6.9% vs 4.0%; HR, 1.77; 95% CI, 1.03‐3.04; P = .04). Subclassification of the clinical presentation of major bleeding events was performed according to prespecified criteria. 54 Severe bleeding at presentation, that is, events considered a medical emergency (category 3; eg, bleeding with hemodynamic instability or intracranial bleeding with neurologic symptoms) or resulting in fatality (category 4), was similar between the treatment arms (2.3% vs 2.5%, respectively). Two fatal bleeding events occurred during the study (both in the dalteparin group) and 6 intracranial hemorrhages (2 in the edoxaban group and 4 in the dalteparin group). A higher rate of gastrointestinal bleeding events (nonemergency; category 2) was observed with edoxaban versus dalteparin therapy (3.8% vs 1.1%, respectively), which occurred primarily in patients with gastrointestinal cancer. However, severe major bleeding (categories 3 and 4) within this subgroup occurred in 3.0% of patients in the edoxaban group and 2.1% of patients within the dalteparin group. 9 , 55 All‐cause mortality at 6 months was 26%, lower than in CATCH (32%) and CLOT (39%), as were the number of patients classed as severely ill (eg, metastatic disease, high ECOG status), and such differences should be kept in mind when interpreting data. It is difficult to compare the outcomes of these studies because they were conducted 15 years apart, and progress made in cancer treatment and supportive care since then may be a confounding factor. 56

SELECT‐D

SELECT‐D (Anticoagulation Therapy in SELECTeD Cancer Patients at Risk of Recurrence of Venous Thromboembolism), the first published randomized trial from the CALLISTO program, was a randomized, open‐label, pilot trial designed to obtain estimates of recurrent VTE in patients with CAT, treated with rivaroxaban or dalteparin therapy, to gauge feasibility of recruitment to a phase III study. Patients with active cancer and objectively confirmed VTE received rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily thereafter) or dalteparin (200 IU/kg once daily for 1 month, 150 IU/kg once daily thereafter [capped at a maximum daily dose of 18 000 IU]). Approximately 80% of patients were treated with a parenteral anticoagulant for the qualifying venous thromboembolic event before randomization to a study drug, with a median treatment duration of 48 hours. 10 Results were similar to those from Hokusai‐VTE‐Cancer, although the difference in statistical power between the 2 studies should be considered when interpreting results: SELECT‐D was much smaller (N = 406) and underpowered for efficacy and safety hypotheses testing.

In SELECT‐D, rivaroxaban demonstrated a reduced risk of VTE recurrence (cumulative rate at 6 months: 4% vs 11%, respectively; HR, 0.43; 95% CI, 0.19‐0.99) compared with dalteparin. The difference in the effect of rivaroxaban compared with dalteparin on VTE recurrence became evident at approximately 2 months after treatment initiation, after the acute treatment phase. Rivaroxaban had a similar risk of major bleeding events, as demonstrated for edoxaban in the Hokusai‐VTE‐Cancer study (cumulative rate at 6 months: 6% vs 4%, for rivaroxaban vs dalteparin, respectively; HR, 1.83; 95% CI, 0.68‐4.96), and the incidence of fatal bleeding events was similar between treatment arms (0.5% vs 0.5%, respectively). No instances of bleeding events in the central nervous system were observed. Most major bleeding events (12/17 [70.6%]) were in the gastrointestinal tract; two‐thirds of these major gastrointestinal bleeds were attributable to rivaroxaban therapy (8/12 [66.7%] with rivaroxaban vs 4/12 [33.3%] with dalteparin). The risk of clinically relevant nonmajor bleeding was also higher with rivaroxaban versus dalteparin therapy (cumulative rate at 6 months: 13% vs 4%, respectively; HR, 3.76; 95% CI, 1.63‐8.69). Of note, patients with esophageal or gastroesophageal cancer were excluded from enrollment partway through the study as a precautionary measure because an interim safety analysis of the first 220 patients noted a nonsignificant excess in the risk of bleeding in these patients. More patients with esophageal or gastroesophageal cancer experienced major bleeding with rivaroxaban (36%) versus dalteparin (5%) therapy. 10

Together, Hokusai‐VTE‐Cancer and SELECT‐D provide evidence that DOACs are effective for CAT treatment, although the higher risk of bleeding with DOACs than with LMWH suggests that careful risk assessment and patient selection are needed. Following these studies, the ISTH has released guidance suggesting edoxaban or rivaroxaban for patients with CAT and a low risk of bleeding and no DDIs with current systemic therapy (LMWHs are an acceptable alternative). 22 LMWH is suggested for patients at high risk of bleeding, including patients with luminal gastrointestinal cancers with an intact primary; cancers at risk of bleeding from genitourinary tract, bladder, or nephrostomy tubes; or patients with active gastrointestinal mucosal abnormalities such as duodenal ulcers, gastritis, esophagitis, or colitis (edoxaban or rivaroxaban are acceptable alternatives if no DDIs with systemic therapies in use). 22 The guidance further states that “a final treatment recommendation should be made after shared decision‐making with patients regarding reduced potential recurrence but greater bleeding rates with specific DOACs, incorporating patient preferences and values.” 22

National Comprehensive Cancer Network guidelines recommend dalteparin monotherapy or LMWH plus edoxaban as category 1 options, with rivaroxaban monotherapy also listed as a category 2A option. 17 They state that “patients may refuse or be poor candidates for LMWH injections because they are painful, inconvenient, and expensive. These factors may contribute to poor compliance with long‐term LMWH treatment.” 17

Whether results from Hokusai‐VTE‐Cancer and SELECT‐D represent a class effect of factor Xa inhibitors will require further evidence. Recently, the randomized, open‐label ADAM VTE (apixaban or dalteparin in reducing blood clots in patients with cancer‐related VTE) safety study (N = 287) reported on the use of apixaban compared with dalteparin for the 6‐month treatment of VTE in patients with active cancer. 11 , 57 The study did not meet its primary end point for major bleeding due to the lower than anticipated number of major bleeding events in both treatment arms (0 of 145 patients receiving apixaban and 1.4% of 142 patients receiving dalteparin). The incidence of recurrent VTE was 0.7% with apixaban and 6.3% with dalteparin (HR, 0.099; 95% CI, 0.013‐0.780; P = .0281). 11 The CARAVAGGIO (apixaban for the treatment of venous thromboembolism in patients with cancer) trial, an investigator‐led, multinational, prospective, randomized trial that is currently ongoing, should provide further insight into the role of apixaban in the treatment of CAT. 13 Table 6 summarizes the key characteristics and data from Hokusai‐VTE‐Cancer, SELECT‐D, and ADAM VTE studies. Additional studies include the single‐arm phase IV CAP (apixaban as treatment of venous thrombosis in patients with cancer) study 58 and others that include dabigatran. 59 , 60

Real‐world evidence for DOACs in the treatment of CAT

Real‐world evidence for DOACs in the treatment of CAT provides additional insights into their use and management, as well as effectiveness, safety, and patient‐reported outcomes associated with use. To date, most of the evidence has been limited to studies of rivaroxaban, 61 , 62 , 63 , 64 , 65 , 66 , 67 whereas real‐world evidence for apixaban in CAT is limited 68 and for dabigatran and edoxaban is currently lacking. When interpreting such data, it is important to note that observational studies are often limited to highly selected and/or small populations of patients with CAT, and that database analyses are limited by retrospective data collection with the possibility of incomplete/missing data.

A Quality Assessment Initiative (QAI) cohort study conducted at Memorial Sloan Kettering Cancer Center (MSKCC) is a prospective real‐world evidence study evaluating rivaroxaban within the CALLISTO program. Following the approval of rivaroxaban for VTE treatment, MSKCC implemented a clinical pathway for rivaroxaban use in CAT. The pathway included patient selection criteria, recommending against rivaroxaban use in patients with known gastrointestinal or urinary tract lesions, untreated primary or metastatic brain cancer, or severe renal impairment. 63 As of October 2016, the QAI study had examined 1072 patients with CAT managed with rivaroxaban in the MSKCC clinical pathway. However, being an observational study, patients were included regardless of compliance with the clinical pathway. 63 , 64 The 6‐month cumulative incidence rate of recurrent VTE was 4.2% (95% CI, 2.7%‐5.7%) and the 6‐month cumulative incidence rate of major bleeding was 2.2% (95% CI, 1.1%‐3.2%); although the recurrent VTE rate was similar to that observed in SELECT‐D, major bleeding was less frequent. 10 , 64 The lower incidence of bleeding in the QAI cohort is likely due to the suggested avoidance/caution with rivaroxaban in patients with known gastrointestinal and genitourinary lesions. SELECT‐D only excluded patients with esophageal and gastroesophageal cancers partway through the study, again highlighting that DOACs are suitable for some but not all patients with cancer.

Results were presented recently on patient‐reported treatment satisfaction from the single‐arm, noninterventional COSIMO (Cancer‐associated thrOmboSIs—patient‐reported outcoMes with rivarOxaban) study, which enrolled patients with cancer and VTE who were changing from LMWH, fondaparinux, or VKA to rivaroxaban therapy for the treatment of CAT. Treatment satisfaction was evaluated through the Anti‐Clot Treatment Scale (ACTS), a 17‐item measure of the negative and positive aspects of anticoagulation treatment, on subscales for ACTS Burdens and ACTS Benefits, respectively. The primary outcome was a change in the ACTS Burdens score at week 4 compared with baseline. Patients with CAT reported a durable improvement in anticoagulation‐associated treatment satisfaction, specifically a reduction in the perceived burdens of therapy, following the change to rivaroxaban. 12 As part of this study, a discrete choice experiment was presented to patients, who were asked to decide between completely hypothetical treatment options based on a combination of different attributes (route of administration [injection/tablet], frequency of intake [once daily/twice daily], need for regular assessment of international normalized ratio at least every 3‐4 weeks [yes/no], and interactions with food/alcohol [yes/no]), regardless of efficacy or safety. Data were collected using semistructured telephone interviews, performed between week 4 and week 12 after enrollment of patients in the study and the start of rivaroxaban administration. This study showed that patients with CAT who changed from standard of care to rivaroxaban primarily preferred to take an orally administered anticoagulant. This is of importance because, so far, little is known about the specific preferences of patients with CAT with respect to anticoagulation therapy. Therefore, individual preferences should be considered for the initiation and long‐term treatment of VTE in patients with CAT because this may result in improved treatment adherence and consequently better effectiveness and safety in routine clinical practice. 69

CURRENT CONTROVERSIES IN CAT

Patient selection strategies for outpatient primary prophylaxis are not well defined

CAT occurs primarily in the outpatient setting, 52 and VTE is a significant cause of death in ambulatory patients with cancer. 70 The benefit–risk profile of antithrombotic prophylaxis among ambulatory patients with cancer is hard to establish because the risk of CAT is highly variable (2%‐20%) and depends on the cancer type, stage, and treatment. 71 , 72 Studies evaluating anticoagulants in this setting have focused on outpatients receiving systemic anticancer therapies but have differed in their approach to patient selection according to VTE risk.

In the SAVE‐ONCO and PROTECHT trials, a significant reduction in the relative risk of VTE with LMWH compared with placebo was demonstrated in mixed cancer‐type populations with no selection for VTE risk. The absolute benefit was modest, meaning that many patients required prophylaxis to prevent a single venous thromboembolic event; therefore, more rigorous selection criteria would be required to identify high‐risk patients who would derive a clinically meaningful benefit from prophylaxis. 49 , 50 In addition, the durations of therapy in these studies were relatively short (~3‐4 months), limiting the ability to adequately assess the value of prophylactic anticoagulation. 49 , 50 Consequently, guidelines do not recommend routine thromboprophylaxis for ambulatory patients with cancer. 16 , 17 , 18 , 19 , 21

Other studies have focused specifically on high‐risk cancer types such as pancreatic cancer and multiple myeloma, 73 , 74 , 75 and based on their outcomes, guidelines suggest consideration of anticoagulant prophylaxis in such patients receiving systemic anticancer therapies. 16 , 17 , 18 , 19 , 21

A third approach has been to enroll a mixed cancer‐type study population limited to patients with a high or intermediate‐to‐high risk of VTE using the Khorana score. 6 , 7 , 76 This widely validated risk‐assessment tool categorizes ambulatory patients with cancer receiving systemic anticancer therapy as being at a low (score 0), medium (score 2), or high (score ≥ 3) risk of VTE. 16 , 17 , 18 , 33 , 77 In a recent retrospective database analysis of over 6000 patients with newly diagnosed cancer who had initiated cancer therapy, patients with a Khorana score ≥ 2 (25% of the study cohort) were 2 to 3 times more likely to develop VTE than those with a score < 2. 78 The AVERT and CASSINI studies limited enrollment to patients with a Khorana score of ≥ 2 and demonstrated that risk‐adapted prophylaxis enables a clinically meaningful absolute risk reduction of VTE. 6 , 7 Based on such evidence, recently published guidelines and guidance endorse the use of the Khorana score to identify patients who may benefit from thromboprophylaxis. 16 , 19 , 21 However, the Khorana score is less informative for assessing the risk of VTE when evaluating patients with lung cancer, as shown in a recent systematic review and meta‐analysis of CAT. 79

Since the validation of the Khorana score, multiple new scores or modifications have been proposed. 80 Pabinger et al 81 proposed a simplified score retaining the original categorization of primary cancer sites but substituted the other variables with only D‐dimer. Comparison of different risk tools is challenging; a prospective comparison of the validated Khorana, Vienna CATS, and PROTECHT prediction scores showed that they were poor at predicting VTE in patients with cancer. 82 However, this study enrolled patients up to several months after starting systemic cancer therapy (instead of obtaining baseline information before chemotherapy initiation), which can affect many variables included in most risk tools (eg, platelet counts). The study results are perhaps unsurprising given this. 82

Duration of anticoagulant therapy for the treatment of CAT remains unclear

Decisions regarding the duration of anticoagulation therapy are central to the secondary prevention of VTE, which involves periodic reassessment of the risk of recurrence if anticoagulation is stopped and the risk of bleeding if it is continued. 20 , 27 The optimal duration of anticoagulation for CAT treatment is particularly challenging. 83 Most guidelines for CAT support extended anticoagulation therapy (≥6 months) for the secondary prevention of VTE, or the continuation of therapy for as long the patient harbors active malignancy (with no scheduled stop date). 16 , 17 , 18 , 19 , 27 The shortcoming of this expert consensus is a paucity of clinical trial data on benefit–risk profile beyond the acute treatment period (3‐6 months). 83 Such data gathering is complicated by the recruitment and retention of patients in extended treatment trials (ie, because of high mortality and a general reluctance to continue treatment beyond 6 months). 10 , 84

The DALTECAN (Evaluation of Dalteparin for Long‐Term [One Year] Treatment of Blood Clots in Subjects With Cancer), TiCAT (Tinzaparin in Cancer‐Associated Thrombosis), and Hokusai‐VTE‐Cancer studies have had some success in evaluating the extended use of anticoagulation for CAT. The primary outcome of the DALTECAN study was the rate of major bleeding between 6 and 12 months of treatment with dalteparin. A total of 334 patients with active cancer and acute VTE were enrolled, with 109 patients (33%) completing 12 months of therapy (the overall mean duration of treatment was 210 days). In total, 116 patients (33.8%) died during the 12‐month study plus 2‐month follow‐up period. The incidence of major bleeding was 3.6% in the first month of treatment, and 1.1% and 0.7% per patient‐month during months 2 through 6 and months 7 through 12, respectively. Similarly, the risk of a recurrent event was highest in the first month, at 5.7%, reducing to 3.4% during months 2‐6 and 4.1% during months 7 through 12. 53 In the TiCAT study, 247 patients were enrolled, with 136 patients (55.1%) completing 12 months of therapy (the overall mean duration of treatment was 15.6 months). Thirty‐nine patients (15.8%) died during the first 6 months and 30 (12.1%) died during the subsequent 12 months. In TiCAT, rates of clinically relevant bleeding (0.6%) and VTE recurrence (1.1%) during months 7 through 12 following the diagnosis of VTE were low; the event rates during months 1‐6 were 0.9% for clinically relevant bleeding and 4.5% for VTE recurrence. 85 In the Hokusai‐VTE‐Cancer study, a total of 1050 patients were enrolled, with 354 (33.8%) of the 1046 patients included in the intention‐to‐treat analysis completing treatment for 12 months or until study closure (the overall median duration of treatment was 211 days for edoxaban and 184 days for dalteparin). A total of 398 patients (38.0%) died over the trial period. As outlined previously, this trial achieved its noninferiority end point for recurrent VTE and major bleeding with edoxaban versus dalteparin. 9 In a post hoc analysis focused on the follow‐up period of 6 to 12 months, rates of recurrent VTE and major bleeding were demonstrated to be low. Recurrent VTE occurred in 2 (0.7%) of 294 patients in the edoxaban group and in 3 (1.1%) of 273 patients in the dalteparin group; major bleeding events occurred in 5 and 3 patients, respectively. 86

However, patients with cancer in the palliative care setting are underrepresented in these clinical trials. Recent data from a multicenter observational study (N = 1199) found a low incidence of VTE (0.5% symptomatic DVT) but a high incidence (9.8%) of clinically relevant bleeding associated with thromboprophylaxis, suggesting that the bleeding risk of VTE prophylaxis might outweigh the benefits in this population. 46 , 87

Further studies regarding extended‐duration CAT treatment would be beneficial but will likely continue to be challenging to obtain. The upcoming DOAC studies for the treatment of CAT—CARAVAGGIO and CONKO‐011 (Rivaroxaban in the Treatment of VTE in Cancer Patients)—are assessing durations of therapy of ≤ 6 months. 13 , 15

There is limited knowledge of drug interactions between anticoagulants and anticancer therapies

Patients with cancer routinely receive numerous co‐medications, including antimitotic agents, tyrosine kinase inhibitors, and immune‐modulating agents, some of which induce or inhibit the activity of cytochrome P450 3A4 enzymes and/or P‐glycoprotein transporters involved in the physiological processing of rivaroxaban and other DOACs. Some patients may even receive combinations of inhibitors and inducers of cytochrome P450 3A4 enzymes and P‐glycoprotein transporters, which further complicates matters. Concomitant medications may increase the risk of bleeding or thrombotic complications with DOAC therapy, depending on the magnitude of the effect on P450 3A4 enzymes and/or P‐glycoproteins. Currently, DOACs have not been shown to have a clinically significant impact on the performance of any antiangiogenic therapies. Frequently used platinum‐based and anticancer hormonal agents do not appear to induce or inhibit cytochrome P450 3A4 or P‐glycoprotein activity 36 ; however, there is limited knowledge of drug interactions between anticoagulants and anticancer therapies because of the ever‐evolving nature of the field. Therefore, careful consideration of potential DDIs and overlapping toxicities using the resources available, along with regular monitoring and reviews of drug combinations on a case‐by‐case basis, is essential.

ONGOING STUDIES IN THE CALLISTO PROGRAM

The CALLISTO international clinical research program, involving more than 3000 patients globally, is investigating the effectiveness and safety of rivaroxaban for prevention and treatment of CAT. Further aims include evaluation of treatment satisfaction and adherence with rivaroxaban and insight into real‐world management and patterns of anticoagulation use. CALLISTO involves several randomized controlled trials (RCTs) and noninterventional studies, as well as expert guidance on DDIs and surveys. Details of ongoing and planned CALLISTO initiatives can be found in Tables 1 and 2 .

CAT prevention

In addition to CASSINI, the CALLISTO program includes another ongoing phase III CAT prevention trial, PRO‐LAPSII (Rivaroxaban or Placebo for Extended Antithrombotic Prophylaxis After Laparoscopic Surgery for Colorectal Cancer). 8 PRO‐LAPSII will assess the rate of CAT with rivaroxaban versus placebo for extended prophylaxis (~3 weeks) after laparoscopic surgery for colorectal cancer. 8 This study will be similar to the PRO‐LAPSI phase III study, which demonstrated reduced rates of CAT and similar rates of major bleeding with extended LMWH prophylaxis (4 weeks) compared with short prophylaxis (1 week). 88

CAT treatment

Efficacy and safety

The CALLISTO program includes several investigator‐led studies assessing the effectiveness and safety of rivaroxaban in CAT treatment. As discussed previously, results from the QAI study 63 and SELECT‐D 10 have been published. A second phase III RCT, CASTA‐DIVA (Cancer Associated Thrombosis, a Pilot Treatment Study Using Rivaroxaban), has recently been completed (pending publication) 14 ; similar to SELECT‐D, this study compared the safety and effectiveness of rivaroxaban and dalteparin for the treatment of CAT. CASTA‐DIVA focused on patients at high risk of recurrent VTE and with high‐grade lymphoma or myeloma treated with immunomodulatory drugs (thalidomide or lenalidomide). 14 The CONKO‐011 study (discussed in more detail below) will also assess the efficacy and safety of rivaroxaban versus LMWH, but as secondary objectives. 15 Other DOAC treatment studies, including CARAVAGGIO 13 for apixaban, are ongoing.

Treatment satisfaction

Several studies have demonstrated patient satisfaction and acceptability of long‐term treatment with LMWH for the treatment of CAT. 89 , 90 , 91 However, real‐world evidence on patient satisfaction with, or preferences for, DOACs in patients with CAT were lacking. The CALLISTO program was developed with an RCT (COSIMO) and a real‐world study (CONKO‐011) to collect data on patient‐reported treatment satisfaction as a primary objective. 15 , 92 The recent results from COSIMO were mentioned in section 3. The phase III clinical trial CONKO‐011 will compare patient‐reported treatment satisfaction in patients after randomization to rivaroxaban or LMWH therapy. 15 , 92 Quality of life will be measured using the Spitzer index, ACTS, and the treatment satisfaction questionnaire for medication.

CAT management and perceptions

Secondary objectives of COSIMO included comprehensive data on cancer type and stage, treatment patterns, and clinical management, including planned treatment duration, switching rates, and reasons for switching or discontinuing therapy. Validated tools for measuring patient fatigue (the Functional Assessment of Chronic Illness Therapy Fatigue score) and for defining the ideal anticoagulant treatment for CAT from the patient perspective have also been used to further inform perceptions of anticoagulants for CAT.

An additional study is the FRONTLINE2 (fundamental research in oncology and thrombosis 2) global survey. 93 It was designed to evaluate how clinicians perceive the risk of VTE in patients with cancer and to provide insights into current strategies for thromboprophylaxis and disease management. Views from oncologists, hematologists, surgeons, radiation oncologists, and members of the palliative care team responsible for treating CAT were collected. A questionnaire (available in 9 languages) was distributed, and the results are currently being analyzed.

CONCLUSIONS

Results from Hokusai‐VTE‐Cancer and SELECT‐D support DOACs (specifically edoxaban and rivaroxaban at present) for treatment of CAT. The results from AVERT and CASSINI demonstrate the potential benefits of thromboprophylaxis with DOACs in the outpatient setting for patients with cancer at higher risk of VTE. 16 , 17 , 19 , 20 , 21 The CALLISTO program, comprising numerous studies, will provide further information on the use of rivaroxaban to simplify the complex management of patients with CAT. It will also evaluate VTE prevention in medically managed patients and surgical patients with active cancer and offer recent data on patient‐reported treatment satisfaction. With many of the CALLISTO studies and other DOAC studies scheduled to be completed over the next couple of years, it is anticipated that the management of CAT will evolve quickly.

CONFLICT OF INTEREST

RB has received personal fees from Bayer AG, Bristol‐Myers Squibb, Pfizer Inc, Daiichi Sankyo, Boehringer Ingelheim, and Leo Pharma. AAK has received personal fees from Janssen Pharmaceuticals, Bayer AG, Pfizer Inc, Sanofi SA, Halozyme Inc, and AngioDynamics Inc. AYYL has received consultancy honoraria from Bayer AG, Pfizer Inc and Leo Pharma, received lecture honoraria from Servier Laboratories and an investigator‐initiated study grant from Bristol‐Myers Squibb. GAS has received consultancy honoraria from Bayer AG and Janssen Pharmaceuticals and has received an investigator‐initiated study grant from Janssen Pharmaceuticals.

ACKNOWLEDGMENTS

The authors thank all members of the CALLISTO Steering Committee for their contributions to the CALLISTO initiative; this manuscript was not reviewed by all members of the CALLISTO steering committee, just the authors listed. The authors also acknowledge Aoife Tracey and Hayley Dawson from Chameleon Communications International Ltd., who provided editorial support, in the form of drafting and fact‐checking the author‐determined content, with funding from Bayer AG and Janssen Scientific Affairs, LLC. The listed authors had the primary role in determining the content of this manuscript.

Bauersachs R, Khorana AA, Lee AYY, Soff G. Cancer‐associated venous thromboembolism: Treatment and prevention with rivaroxaban. Res Pract Thromb Haemost. 2020;4:532–549. 10.1002/rth2.12327

Handling Editor: Susan Kahn

Contributor Information

Rupert Bauersachs, Email: bauersachs@em.uni-frankfurt.de.

Alok A. Khorana, @aakonc.

Agnes Y. Y. Lee, @AggieLeeMD.

REFERENCES

1. Bach M, Bauersachs R. Spotlight on advances in VTE management: CALLISTO and EINSTEIN CHOICE. Thromb Haemost. 2016;116:S24–32.

2. Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484–8.

3. Fuentes HE, Tafur AJ, Caprini JA. Cancer‐associated thrombosis. Dis Mon. 2016;62:121–58.

4. Lyman GH. Venous thromboembolism in the patient with cancer: focus on burden of disease and benefits of thromboprophylaxis. Cancer. 2011;117:1334–49.

5. Khalil J, Bensaid B, Elkacemi H, et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J Surg Oncol. 2015;13:204.

6. Khorana AA, Soff GA, Kakkar AK, Vadhan‐Raj S, Riess H, Wun T, et al. Rivaroxaban for thromboprophylaxis in high‐risk ambulatory patients with cancer. N Engl J Med. 2019;380:720–8.

7. Carrier M, Abou‐Nassar K, Mallick R, et al. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019;380:711–9.

8. Fadoi Foundation . Rivaroxaban or placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. (PRO‐LAPSII). 2018. [Accessed 17 July 2019]. Available from https://clinicaltrials.gov/ct2/show/NCT03055026

9. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer‐associated venous thromboembolism. N Engl J Med. 2018;378:615–24.

10. Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral Factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT‐D). J Clin Oncol. 2018;36:2017–23.

11. McBane RD, Wysokinski WE, Le‐Rademacher JG, et al. Apixaban and dalteparin in active malignancy associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost. 2019;18(2):411–21.

12. Cohen AT, Maraveyas A, Beyer‐Westendorf J, et al. Patient‐reported outcomes associated with switching to rivaroxaban for the treatment of venous thromboembolism (VTE) in patients with active cancer. Ann Oncol. 2019;30:v724–v725.

13. Agnelli G, Becattini C, Bauersachs R, et al. Apixaban versus dalteparin for the treatment of acute venous thromboembolism in patients with cancer: the Caravaggio study. Thromb Haemost. 2018;118:1668–78.

14. Assistance Publique – Hôpitaux de Paris . Cancer associated thrombosis, a pilot treatment study using rivaroxaban (CASTA‐DIVA). 2018. [Accessed 12 August 2019]. Available from https://clinicaltrials.gov/ct2/show/NCT02746185

15. AIO‐Studien‐gGmbH . Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. 2018 [accessed 12 August 2019]. Available from https://clinicaltrials.gov/ct2/show/study/NCT02583191

16. Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2019;38(5):496–520.

17. National Comprehensive Cancer Network . Cancer‐associated venous thromboembolic disease, version 1.2019. Plymouth Meeting, PA, USA: National Comprehensive Cancer Network, Inc. 2019. [Accessed 12 August 2019] Available from https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf

18. Mandalà M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;6:vi85–92.

19. Farge D, Frere C, Connors JM, Ay C, Khorana AA, Munoz A, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol. 2019;20:e566–e581.

20. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G‐J, Harjola V‐P, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41:543–603.

21. Wang T‐F, Zwicker JI, Ay C, Pabinger I, Falanga A, Antic D, et al. The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2019;17:1772–8.

22. Khorana AA, Noble S, Lee AYY, Soff G, Meyer G, O'Connell C, et al. Role of direct oral anticoagulants in the treatment of cancer‐associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16:1891–4.

23. Lee AYY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low‐molecular‐weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53.

24. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180‐day period. Clin Appl Thromb Hemost. 2006;12:389–96.

25. Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, et al. Treatment of proximal deep‐vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa‐DVT (Oral Direct Factor Xa Inhibitor BAY 59–7939 in patients with acute symptomatic Deep‐Vein Thrombosis) study. Circulation. 2007;116:180–7.

26. Lee AYY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA. 2015;314:677–86.

27. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52.

28. Mantha S, Miao Y, Wills J, Parameswaran R, Soff A. Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study. J Thromb Thrombolysis. 2017;43:514–8.

29. Wharin C, Tagalakis V. Management of venous thromboembolism in cancer patients and the role of the new oral anticoagulants. Blood Rev. 2014;28:1–8.

30. Khorana AA, Yannicelli D, McCrae KR, Milentijevic D, Crivera C, Nelson WW, et al. Evaluation of US prescription patterns: Are treatment guidelines for cancer‐associated venous thromboembolism being followed? Thromb Res. 2016;145:51–3.

31. Khorana A, McCrae K, Milentijevic D, McCormick N, Lalliberte F, Crivera C, et al. Anticoagulant treatment patterns for cancer‐associated thrombosis in a commercial insurance population. Circulation. 2017;136:15539.

32. Khorana AA, McCrae KR, Milentijevic D, Fortier J, Nelson WW, Laliberté F, et al. Current practice patterns and patient persistence with anticoagulant treatments for cancer‐associated thrombosis. Res Pract Thromb Haemost. 2017;1:14–22.

33. Khorana AA, Carrier M, Garcia DA, Lee AYY. Guidance for the prevention and treatment of cancer‐associated venous thromboembolism. J Thromb Thrombolysis. 2016;41:81–91.

34. Vedovati MC, Giustozzi M, Bonitta G, Agnelli G, Becattini C. Efficacy and safety of anticoagulant agents in patients with venous thromboembolism and cancer: A network meta‐analysis. Thromb Res. 2018;170:175–80.

35. Carrier M, Cameron C, Delluc A, Castellucci L, Khorana AA, Lee AY. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer‐associated thrombosis: a systematic review and meta‐analysis. Thromb Res. 2014;134:1214–9.

36. Short NJ, Connors JM. New oral anticoagulants and the cancer patient. Oncologist. 2014;19:82–93.

37. Mekaj YH, Mekaj AY, Duci SB, Miftari EI. New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag. 2015;11:967–77.

38. Riechelmann RP, Del Giglio A. Drug interactions in oncology: how common are they? Ann Oncol. 2009;20:1907–12.

39. Jakobsen CB, Lamberts M, Carlson N, Lock‐Hansen M, Torp‐Pedersen C, Gislason GH, et al. Incidence of atrial fibrillation in different major cancer subtypes: a Nationwide population‐based 12 year follow up study. BMC Cancer. 2019;19:1105.

40. Conen D, Wong JA, Sandhu RK, Cook NR, Lee I‐M, Buring JE, et al. Risk of malignant cancer among women with new‐onset atrial fibrillation. JAMA Cardiol. 2016;1:389–96.

41. Navi BB, Reiner AS, Kamel H, Iadecola C, Okin PM, Elkind MSV, et al. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol. 2017;70:926–38.

42. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37:2893–962.

43. January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC Jr, Cigarroa JE, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64:e1–76.

44. Patell R, Gutierrez A, Rybicki L, Khorana A. Usefulness of CHADS 2 and CHA 2 DS 2 ‐VASc scores for stroke prediction in patients with cancer and atrial fibrillation. Am J Cardiol. 2017;120:2182–6.

45. Ording AG, Horváth‐Puho E, Adelborg K, Pedersen L, Prandoni P, Sørensen HT. Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population‐based cohort study. Cancer Med. 2017;6:1165–72.

46. Delluc A, Wang TF, Yap ES, Ay C, Schaefer J, Carrier M, et al. Anticoagulation of cancer patients with non‐valvular atrial fibrillation receiving chemotherapy: Guidance from the SSC of the ISTH. J Thromb Haemost. 2019;. 10.1111/jth.14478.

47. Schünemann HJ, Cushman M, Burnett AE, Kahn SR, Beyer‐Westendorf J, Spencer FA, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv. 2018;2:3198–225.

48. Anderson DR, Morgano GP, Bennett C, Dentali F, Francis CW, Garcia DA, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3:3898–944.

49. Agnelli G, George DJ, Kakkar AK, Fisher W, Lassen MR, Mismetti P, et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012;366:601–9.

50. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna L, et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo‐controlled, double‐blind study. Lancet Oncol. 2009;10:943–9.

51. Kimpton M, Wells PS, Carrier M. Apixaban for the prevention of venous thromboembolism in high‐risk ambulatory cancer patients receiving chemotherapy: rational and design of the AVERT trial. Thromb Res. 2018;164(Suppl 1):S124–S129.

52. Khorana A, Vadhan‐Raj S, Kuderer N, Wun T, Liebman H, Soff G, et al. Rivaroxaban for preventing venous thromboembolism in high‐risk ambulatory patients with cancer: rationale and design of the CASSINI trial. Rationale and design of the CASSINI trial. Thromb Haemost. 2017;117:2135–45.

53. Francis CW, Kessler CM, Goldhaber SZ, Kovacs MJ, Monreal M, Huisman MV, et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost. 2015;13:1028–35.

54. Bleker S, Brekelmans M, Eerenberg E, Cohen A, Middeldorp S, Raskob G, et al. Clinical impact of major bleeding in patients with venous thromboembolism treated with Factor Xa inhibitors or vitamin K antagonists. Thromb Haemost. 2017;117:1944–51.

55. Kraaijpoel N, Di Nisio M, Mulder F, van Es N, Beyer‐Westendorf J, Carrier M, et al. Clinical impact of bleeding in cancer‐associated venous thromboembolism: results from the Hokusai VTE Cancer study. Thromb Haemost. 2018;118:1439–49.

56. Imberti D, Cimminiello C, Di Nisio M, Marietta M, Polo Friz H, Ageno W. Antithrombotic therapy for venous thromboembolism in patients with cancer: expert guidance. Expert Opin Pharmacother. 2018;19:1177–85.

57. McBane R, Loprinzi C, Ashrani A, Botero JP, Leon Ferre R, Henkin S, et al. Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE trial. Thromb Haemost. 2017;117:1952–61.

58. University Hospital Akershus . Apixaban as treatment of venous thrombosis in patients with cancer: the CAP study. 2018. [Accessed 17 July 2019] Available from https://clinicaltrials.gov/ct2/show/study/NCT02581176

59. The University of Hong Kong . A study of dabigatran etexilate as primary treatment of malignancy associated venous thromboembolism. 2017. [Accessed 17 July 2019] Available from https://clinicaltrials.gov/ct2/show/NCT03240120

60. Alliance Foundation Trials LLC, Patient‐Centered Outcomes Research Institute . Direct oral anticoagulants versus LMWH +/‐ warfarin for VTE in cancer (CANVAS). 2018. [Accessed 16 December 2019] Available from https://clinicaltrials.gov/ct2/show/NCT02744092

61. Khorana AA, McCrae K, Milentijevic D, McCormick N, Laliberté F, Crivera C, et al. The risk of recurrent VTE and major bleeding in a commercially‐insured population of cancer patients treated with anticoagulation. Am J Hematol. 2019;94:E58E61.

62. Simmons B, Wysokinski W, Saadiq RA, Bott‐Kitslaar D, Henkin S, Casanegra A, et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer‐associated venous thromboembolism. Eur J Haematol. 2018;. 10.1111/ejh.13074.

63. Mantha S, Laube E, Miao Y, Sarasohn DM, Parameswaran R, Stefanik S, et al. Safe and effective use of rivaroxaban for treatment of cancer‐associated venous thromboembolic disease: a prospective cohort study. J Thromb Thrombolysis. 2017;43:166–71.

64. Soff GA, Mones J, Wilkins CY, Devlin S, Haegler‐Laube E, Wills J, et al. Rivaroxaban treatment of cancer‐associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience. Res Pract Thromb Haemost. 2019;3:349–56.

65. Ageno W, Mantovani L, Haas S, Kreutz R, Monje D, Schneider J, et al. Subgroup analysis of patients with cancer in XALIA: a noninterventional study of rivaroxaban versus standard anticoagulation for VTE. TH Open. 2017;1:e33–e42.

66. Streiff MB, Milentijevic D, McCrae K, Yannicelli D, Fortier J, Nelson WW, et al. Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018;93:664–71.

67. Kohn CG, Lyman GH, Beyer‐Westendorf J, Spyropoulos AC, Bunz TJ, Baker WL, et al. Effectiveness and safety of rivaroxaban in patients with cancer‐associated venous thrombosis. J Natl Compr Canc Netw. 2018;16:491–S7.

68. Wysokinski WE, Houghton DE, Casanegra AI, Vlazny DT, Bott‐Kitslaar DM, Froehling DA, et al. Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer‐associated venous thromboembolism. Am J Hematol. 2019;94:1185–92.

69. Picker N, Cohen AT, Maraveyas A, et al. Patient preferences regarding anticoagulation therapy in patients with cancer having a VTE event ‐ a Discrete Choice Experiment in the COSIMO study. Blood. 2019;34(Supplement_1):2159.

70. Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632–4.

71. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta‐analysis. PLoS Med. 2012;9:e1001275.

72. Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population‐based cohort study. Thromb Haemost. 2017;117:57–65.

73. Pelzer U, Opitz B, Deutschinoff G, Stauch M, Reitzig PC, Hahnfeld S, et al. Efficacy of prophylactic low‐molecular weight heparin for ambulatory patients with advanced pancreatic cancer: outcomes from the CONKO‐004 trial. J Clin Oncol. 2015;33:2028–34.

74. Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012;48:1283–92.

75. Swan D, Rocci A, Bradbury C, Thachil J. Venous thromboembolism in multiple myeloma ‐ choice of prophylaxis, role of direct oral anticoagulants and special considerations. Br J Haematol. 2018;183:538–56.

76. Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, et al. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: a randomized trial. Thromb Res. 2017;151:89–95.

77. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy‐associated thrombosis. Blood. 2008;111:4902–7.

78. Khorana AA, Kuderer NM, McCrae KR, Milentijevic D, Germain G, Laliberté F, et al. The rate of venous thromboembolism in cancer patients varies by Khorana risk category. Blood. 2018;132:3798.

79. Mulder FI, Candeloro M, Kamphuisen PW, Di Nisio M, Bossuyt PM, Guman N, et al. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta‐analysis. Haematologica. 2019;104:1277–87.

80. Khorana AA. Simplicity versus complexity: an existential dilemma as risk tools evolve. Lancet Haematol. 2018;5:e273–e4.

81. Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter E‐M, et al. A clinical prediction model for cancer‐associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol. 2018;5:e289–e98.

82. van Es N, Di Nisio M, Cesarman G, Kleinjan A, Otten H‐M, Mahé I, et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica. 2017;102:1494–501.

83. Lee AYY. When can we stop anticoagulation in patients with cancer‐associated thrombosis? Blood. 2017;130:2484–90.

84. Noble SI, Nelson A, Fitzmaurice D, Bekkers MJ, Baillie J, Sivell S, et al. A feasibility study to inform the design of a randomised controlled trial to identify the most clinically effective and cost‐effective length of Anticoagulation with Low‐molecular‐weight heparin In the treatment of Cancer‐Associated Thrombosis (ALICAT). Health Technol Assess. 2015;vii–xxiii:1–93.

85. Jara‐Palomares L, Solier‐Lopez A, Elias‐Hernandez T, Asensio‐Cruz M, Blasco‐Esquivias I, Marin‐Barrera L, et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res. 2017;157:90–6.

86. Di Nisio M, van Es N, Carrier M, Wang TF, Garcia D, Segers A, et al. Extended treatment with edoxaban in cancer patients with venous thromboembolism: A post‐hoc analysis of the Hokusai‐VTE Cancer study. J Thromb Haemost. 2019. 10.1111/jth.14561.

87. Tardy B, Picard S, Guirimand F, Chapelle C, Danel Delerue M, Celarier T, et al. Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study. J Thromb Haemost. 2017;15:420–8.

88. Vedovati MC, Becattini C, Rondelli F, Boncompagni M, Camporese G, Balzarotti R, et al. A randomized study on 1‐week versus 4‐week prophylaxis for venous thromboembolism after laparoscopic surgery for colorectal cancer. Ann Surg. 2014;259:665–9.

89. Noble SI, Finlay IG. Is long‐term low‐molecular‐weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Palliat Med. 2005;19:197–201.

90. Cajfinger F, Debourdeau P, Lamblin A, Benatar V, Falvo N, Benhamou Y, et al. Low‐molecular‐weight heparins for cancer‐associated thrombosis: adherence to clinical practice guidelines and patient perception in TROPIQUE, a 409‐patient prospective observational study. Thromb Res. 2016;144:85–92.

91. Seaman S, Nelson A, Noble S. Cancer‐associated thrombosis, low‐molecular‐weight heparin, and the patient experience: a qualitative study. Patient preference and adherence. 2014;8:453–61.

92. Cohen AT, Maraveyas A, Beyer‐Westendorf J, Lee AYY, Mantovani LG, Bach M, et al. COSIMO ‐ patients with active cancer changing to rivaroxaban for the treatment and prevention of recurrent venous thromboembolism: a non‐interventional study. Thromb J. 2018;16:21.

93. Hart Wilcox . Frontline2: Fundamental research in oncology and thrombosis. 2018. [Accessed 17 July 2019] Available from http://frontline2.tri‐london.ac.uk/