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Thursday 27 June 2019
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Oral anticoagulants and cancer-associated thrombosis

Venous thromboembolism (VTE) is a frequent complication in patients with cancer.1–3 About 8% of cancer patients will develop VTE during their disease.4 VTE is associated with higher risks of bleeding and recurrence during anticoagulant treatment in patients with cancer than in other patients.5
 

Low molecular weight heparins

A series of trials have shown that prolonged treatment with low molecular weight heparin (LMWH) given for at least three to six months is associated with a reduction in the risk of recurrent VTE as compared with the traditional treatment regimen with LMWH overlapped and followed by vitamin K antagonists (VKA) in patients with cancer-associated thrombosis (CAT).6 Even with LMWH, about 7% of patients with CAT experience recurrent VTE during the first six months of treatment.7 The prolonged use of LMWH is associated with the need of daily subcutaneous injections, bruising at the injection site and a higher cost than VKA. In clinical practice, a significant proportion of patients with CAT continue receiving VKA.8 Most of the patients with CAT have a significant risk of recurrent VTE after the initial six-month treatment and anticoagulation needs to be prolonged for more than six months in a significant number of these patients making the use of subcutaneous treatment even more difficult.9
 

NOACs

Non-vitamin K oral anticoagulants (NOACs) are direct inhibitors of factor IIa or factor Xa. These drugs have a predictable anticoagulant effect and do not need monitoring; they have an early onset of action with peak plasma concentrations obtained about 3–4 hours after ingestion. Rivaroxaban and apixaban can be administered in the acute phase of VTE without any preceding parenteral anticoagulation, whereas dabigatran and edoxaban have been tested after at least five days of treatment with LMWH.10–13 In a series of six randomised controlled trials on approximately 26,000 patients with VTE, NOACs were effective (relative risk (RR) 0.90; 95% CI 0.77–1.06 for first recurrent VTE or VTE-related death) and safer than VKA (RR 0.61; 95% CI 0.45–0.83 for major bleeding) in patients with VTE.14
 
A minority of patients included in these trials had underlying cancer. Meta-analyses of this subgroup of patients with CAT show that DOACs are associated with a non-significant reduction in the risk of recurrent VTE (RR 0.65, 95% CI 0.38–1.09) and bleeding (RR, 0.67, 95% CI 0.31–1.46) as compared with VKA.6
 
Of note, cancer patients in these trials had less advanced cancer, a smaller proportion received anticancer treatment and the mortality was lower than in the trials comparing LMWH and VKA in patients with CAT. The reference treatment (VKA) in these trials was not the most appropriate for patients with CAT.
 
Several observational cohort studies have been published describing initial experiences with NOACs in patients with CAT and have been summarised in a systematic review.15 Most studies used rivaroxaban and enoxaparin. The on-treatment duration of NOACs was longer than that of LMWH. All studies except one reported lower rates of recurrent VTE for patients using NOAC as compared with those on LMWH, but these results may be attributable to patient selection. Because of the observational design, patients were not randomised to receive one of the two treatments and the treatment groups are not comparable. 
 
In most studies, the outcomes were not assessed independently. The bleeding outcomes were heterogeneous across different studies with two studies that only included gastrointestinal and gynaecological cancers reporting higher rates of major bleeds in patients receiving a NOAC.16,17
 

Clinical trials

Two randomised clinical trials comparing prolonged treatment with LMWH and a NOACin patients with CAT have been reported.
 

HOKUSAI Cancer

HOKUSAI Cancer was an open-label, non-inferiority trial that randomised 1050 patients with CAT to LMWH for at least five days followed by oral edoxaban 60mg once daily or dalteparin 200IU/kg daily, for one month followed by 150 IU/kg daily during months 2–12.18 Study drug was given for at least 6 and up to 12 months and all patients were followed for 12 months. The primary outcome was a composite of recurrent VTE or major bleeding during 12 months after randomisation and occurred in 12.8% of the patients allocated to receive edoxaban and in 13.5% of those who were randomised to dalteparin (HR 0.97; 95% CI 0.70−1.36). 
 
Recurrent VTE occurred in 7.9% of patients who were receiving edoxaban and in 11.3% of those allocated to dalteparin (difference in risk −3.4%; 95% CI −7.0−0.2). Major bleeding occurred in 6.9% of the patients in the edoxaban arm and in 4.0% of patients randomised to receive dalteparin (difference in risk 2.9%; 95% CI 0.1−5.6). Most of the difference in major bleeding was related to gastrointestinal and urogenital bleeding and the increase in the risk of major bleeding was especially high in gastrointestinal cancers. The median duration of the assigned treatment was 211 days in the edoxaban group and 184 days in the dalteparin group (p = 0.01); more patients in the dalteparin group stopped trial medication because of inconvenience of dosing. 
 
Trial medication was to be continued for at least six months. During this period, the primary outcome of recurrent VTE or major bleeding occurred in 10.5% and 10.7% in patients who were receiving edoxaban and dalteparin, respectively (hazard ratio (HR) 1.01; 95%CI 0.69−1.46).18
 

Select-D

Select-D was a prospective, randomised, open label trial comparing dalteparin (200IU/kg daily, during the first month, followed by 150IU/kg daily, during months two to six); and rivaroxaban (15mg twice daily for three weeks followed by 20mg once daily, for six months) in 406 patients with cancer and VTE. The VTE recurrence rate at six months was 11% (95% CI 7−17%) for patients on dalteparin and 4% (95% CI 2−9%) for patients on rivaroxaban (HR 0.43; 95% CI 0.19−0.99). Major bleeding occurred in 4% (95% CI 2−8%) of the patients in the dalteparin and 6% (95% CI 3−11%) in the patients allocated to rivaroxaban (HR 1.83; 95% CI 0.68−4.96). 
 
Corresponding rates of CRNMB were 4% (95% CI 2−9%) and 13% (95% CI 9−19%), respectively (HR 3.76; 95% CI 1.63−8.69).19 There were more clinically relevant non-major bleedings in the rivaroxaban arm (13%; 95% CI 9−19%) than in the dalteparin arm (2%; 95% CI 1−6%). In total, 5% (95% CI 3−9%) of patients in the dalteparin arm had either major or non-major clinically significant bleeding as compared to 17% (95% CI 12−22%) of the patients in the rivaroxaban arm.19 A meta-analysis of these two studies concluded that NOACs are associated with a lower risk of recurrent VTE than LMWH at six months (RR 0.65; 95% CI 0.42−1.01) but are associated with a higher risk of major bleeding (RR 1.74; 95% CI 1.05−2.88) and a higher risk of clinically relevant non-major bleeding than LMWH (RR 2.31; 95% CI 0.85−6.28).15
    
The current data regarding the effectiveness of NOACS in patients with CAT remain limited. The comparison with VKA in the Phase III trials is reassuring but the patients included in these studies had less aggressive or less extensive cancer than those included in the LMWH trials. Data from observational cohort studies are limited by the lack of adequate control groups and the lack of blinded adjudication of outcomes, in these studies, a selection bias favouring NOACs cannot be excluded. 
 
The lower rate of recurrent VTE with NOACS suggested in these observational cohort studies seems to be confirmed in the two first randomised trials comparing NOACs with LMWH in patients with CAT, although the difference was not significant in either of the two studies. Conversely, an increase in the bleeding risk has been observed in the two trials in the patients who were randomised to receive a NOAC. These results, observed with rivaroxaban and edoxaban, remain to be confirmed for dabigatran and apixaban. 
 

Conclusions

Several ongoing randomised controlled trials will probably shed more light on the role of NOACs in patients with CAT. Pending the results of these trials, NOACs might be considered as an alternative to LMWH for the treatment of CAT in patients without gastrointestinal or urogenital cancer and who do not have an increased bleeding risk. NOACs may also be considered as an option in patients who do not tolerate the daily injections of LMWH and in patients who need prolonged anticoagulant treatment after six months of treatment with LMWH.
 

References

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4 Ay C et al. D-dimer and prothrombin fragment 1 + 2 predict venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2009;27:4124–9.
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15 Li A et al. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res 2018; Mar 2. pii: S0049-3848(18)30216-0.
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17 Seo S et al. Oral rivaroxaban versus subcutaneous low molecular weight heparin treatment for venous thromboembolism in patients with upper gastrointestinal, hepatobiliary and pancreatic cancer. Ann Oncol 2016;27:vi207–vi42.
18 Raskob GE et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615–24.
19 Young A et al. Anticoagulation therapy in 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.