Direct oral anticoagulants for the treatment of cancer-associated thrombosis

Cancer-associated venous thromboembolism (VTE) is known to impact up to one-fifth of patients with cancer. The treatment of cancer-associated VTE is complicated by both high rates of recurrent VTE as well as high rates of bleeding.   Since 2003, low-molecular-weight heparin (LMWH) monotherapy for at least six months after diagnosis of either deep vein thrombosis (DVT) or pulmonary embolism (PE) has been the standard of care. However, this standard has been challenged by emerging new data for the class of agents known as direct oral anticoagulants (DOACs).

Two major randomized trials as well as a wealth of real-world data has impacted clinical practice. It is important to consider not simply trials evidence but also clinical practice data for context and for knowledge regarding patient preferences, outside of a trial setting.

Real-world data

Two major cancer institutions in the United States switched to rivaroxaban for primary treatment of cancer-associated VTE even prior to randomized data in cancer patients. A recent updated report from one of these, Memorial Sloan Kettering, provides data from 2014 through 2016, when 1072 patients began rivaroxaban treatment^[1]. The 6-month cumulative incidence of recurrent VTE and major bleeding were 4.2% (95% confidence interval [CI], 2.7%-5.7%) and 2.2% (95% CI, 1.1%-3.2%), respectively. The incidence of clinically relevant non-major bleeding leading to discontinuation of rivaroxaban for at least 7 days was 5.5% (95% CI, 3.7%-7.1%), and 73.3% of major bleeds occurred in the GI tract. A smaller series was reported by the Mayo Clinic^[2]. Of 98 patients treated with rivaroxaban and 168 with enoxaparin, there were no differences in 3-month VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all-cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). Together, these data suggest that DOACs can be safe and effective in clinical practice, with appropriate patient selection.

Randomized trials

Two major randomized trials have advanced knowledge in this setting. The Hokusai VTE Cancer study was a randomized, open-label, non-inferiority trial of 1,050 cancer patients with acute VTE given LMWH for at least 5 days followed by randomization to either oral edoxaban 60 mg daily or dalteparin 200 IU/kg daily in month 1 and 150 IU/kg for 2 up to12 months^[3]. The primary outcome – a combination of recurrent VTE or major bleeding in 12 months – was seen in 12.8% of patients randomized to edoxaban arm and 13.5% in the dalteparin arm (HR 0.97; 95% CI 0.70–1.36; p = 0.006 for non-inferiority). Excess bleeding was noted in the edoxaban arm, but the majority of patients with clinically meaningful bleeding events had gastrointestinal cancers (particularly gastro-esophageal and colorectal). Select-D was also a prospective, randomized, open-label, multicenter study with 406 cancer patients with acute VTE randomized to either dalteparin (200 IU/kg daily in month 1, and 150 IU/kg in months 2–6) or rivaroxaban (15 mg twice daily for 3 weeks, and then 20 mg once daily, for 6 months)^[4]. Patients randomized to rivaroxaban had lower VTE recurrence (4% versus 11%, 95% CI 7–16% versus 2–9%) at six months. Major bleeding, similar to Hokusai, was higher with rivaroxaban (6% versus 4%, 95% CI 2–8% vs 3–11%). A majority of patients with bleeding events had gastrointestinal cancers (primarily, esophageal or gastro-esophageal). Studies with apixaban are ongoing, with initial pilot data consistent with the already published literature in DOACs.

Guidelines

Three major guidelines panels have taken into account the new data and provided guidance to clinicians regarding best approaches to treatment of VTE in patients with cancer. The International Society of Thrombosis and Haemostasis (ISTH) guidance statement suggeststhe use of edoxaban or rivaroxaban in cancer patients with VTE at low risk for bleeding, incorporating patient preferences and values^[5]. LMWH monotherapy continues to be an alternative, and is preferentially recommended in patients at high risk of bleeding. The American Society of Clinical Oncology (ASCO) guidelines were also revised recently^[6]. For treatment, approaches to initial anticoagulation endorsed by ASCO include LMWH, unfractionated heparin, fondaparinux, or rivaroxaban. For long-term anticoagulation, ASCO guidelines recommend LMWH, edoxaban, or rivaroxaban for at least 6 months as preferred because of improved efficacy over vitamin K antagonists (VKAs). VKAs are inferior but may be used if LMWH or direct oral anticoagulants (DOACs) are not accessible. The guidelines note that there is an increase in major bleeding risk with DOACs, particularly in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOACs.

The international clinical practice guidelines (ITAC) were also recently revised in light of new data⁷. These guidelines recommend DOACs for patients with cancer when creatinine clearance is ≥30 mL/min in the absence of strong drug–drug interactions or gastrointestinal absorption impairment (grade 1A). The authors advise caution in patients with gastrointestinal tract malignancies, especially upper gastrointestinal tract, as the available data show increased risk of gastrointestinal tract bleeding with edoxaban and rivaroxaban. LMWHs are preferred over vitamin K antagonists for the treatment of VTE in patients with cancer when creatinine clearance is ≥30 mL/min (grade 1A). Data for other direct oral anticoagulants are needed as it is not clear whether other direct oral anticoagulants will have the same risk profile

Overall, this change in treatment approaches is a major and meaningful advance for the field. The availability of multiple options allows clinicians to individualize treatment. With appropriate patient selection and compliance, over 90% of patients will have neither recurrent VTE nor major bleeding. This is truly a meaningful outcome for patients.

References

1. Soff GA, Mones J, Wilkins C, et al. Rivaroxaban treatment of cancer-associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience. Research and practice in thrombosis and haemostasis 2019;3:349-56.
2. Simmons B, Wysokinski W, Saadiq RA, et al. Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism. European journal of haematology 2018.
3. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. The New England journal of medicine 2018;378:615-24.
4. 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.
5. Khorana AA, Noble S, Lee AYY, 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.
6. 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:JCO1901461.
7. Farge D. , Frere C., Connors JM et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019.